Next Article in Journal
NHERF1 Enhances Cisplatin Sensitivity in Human Cervical Cancer Cells
Next Article in Special Issue
The Role of Inhaled Loxapine in the Treatment of Acute Agitation in Patients with Psychiatric Disorders: A Clinical Review
Previous Article in Journal
Shp2 Inhibits Proliferation of Esophageal Squamous Cell Cancer via Dephosphorylation of Stat3
Previous Article in Special Issue
d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions

by
Carmine Tomasetti
1,2,3,*,
Felice Iasevoli
2,3,
Elisabetta Filomena Buonaguro
2,3,
Domenico De Berardis
3,4,5,
Michele Fornaro
3,6,
Annastasia Lucia Carmela Fiengo
3,
Giovanni Martinotti
3,5,
Laura Orsolini
3,7,
Alessandro Valchera
3,7,
Massimo Di Giannantonio
5 and
Andrea De Bartolomeis
2
1
NHS, Department of Mental Health ASL Teramo, Psychiatric Service of Diagnosis and Treatment, Hospital “Maria SS dello Splendore”, 641021 Giulianova, Italy
2
Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, Reproductive and Odontostomatogical Sciences, University of Naples “Federico II”, 80131 Napoli, Italy
3
Polyedra Research Group, 64100 Teramo, Italy
4
NHS, Department of Mental Health ASL Teramo, Psychiatric Service of Diagnosis and Treatment, Hospital “G. Mazzini”, 64100 Teramo, Italy
5
Department of Neuroscience and Imaging, University “G. d’Annunzio”, 66100 Chieti, Italy
6
New York State Psychiatric Institute, Columbia University, New York, NY 10027, USA
7
Casa di Cura Villa San Giuseppe, 63100 Ascoli Piceno, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(1), 135; https://doi.org/10.3390/ijms18010135
Submission received: 27 November 2016 / Revised: 25 December 2016 / Accepted: 8 January 2017 / Published: 12 January 2017
(This article belongs to the Special Issue Antipsychotics)

Abstract

:
Dopamine-glutamate interplay dysfunctions have been suggested as pathophysiological key determinants of major psychotic disorders, above all schizophrenia and mood disorders. For the most part, synaptic interactions between dopamine and glutamate signaling pathways take part in the postsynaptic density, a specialized ultrastructure localized under the membrane of glutamatergic excitatory synapses. Multiple proteins, with the role of adaptors, regulators, effectors, and scaffolds compose the postsynaptic density network. They form structural and functional crossroads where multiple signals, starting at membrane receptors, are received, elaborated, integrated, and routed to appropriate nuclear targets. Moreover, transductional pathways belonging to different receptors may be functionally interconnected through postsynaptic density molecules. Several studies have demonstrated that psychopharmacologic drugs may differentially affect the expression and function of postsynaptic genes and proteins, depending upon the peculiar receptor profile of each compound. Thus, through postsynaptic network modulation, these drugs may induce dopamine-glutamate synaptic remodeling, which is at the basis of their long-term physiologic effects. In this review, we will discuss the role of postsynaptic proteins in dopamine-glutamate signals integration, as well as the peculiar impact of different psychotropic drugs used in clinical practice on postsynaptic remodeling, thereby trying to point out the possible future molecular targets of “synapse-based” psychiatric therapeutic strategies.

1. Introduction

The post-synaptic density (PSD) is a specialized matrix located at excitatory post-synaptic terminals with a disc-shaped aspect, a surface area of 0.07 μm2 and a thickness of 30–40 nm at the electron microscopy [1].
The PSD can be described as a macromolecular complex of several hundreds of proteins acting as a molecular switchboard of multiple interacting neurotransmitter signaling pathways [2,3,4].
Results from PSD preparations obtained with different proteomic purification essays have revealed that more than 400 proteins can be regularly found by mass spectrometry fingerprinting in the PSD proteome [5]. These proteins include: membrane receptors and channels, signaling proteins, scaffold and anchoring proteins, GTPases and regulator proteins, kinases, and phosphatases, cytoskeleton proteins [1,6,7].
PSD molecules are involved in several functions critical to dopamine and glutamate-dependent synaptic plasticity processes at glutamatergic synapses [8,9]. Indeed, N-Methyl-d-Aspartate (NMDA) receptors represent the core of this protein mesh, whilst non-NMDA ionotropic and metabotropic glutamate receptors are located at the edge of the PSD [1]. Specifically, glutamatergic receptors are targeted at the postsynaptic membrane by PSD multiprotein complexes that regulate their clustering, signal-transduction activity and therefore synaptic rearrangements [10].
Intriguingly, mass spectroscopy evaluations have provided the possibility to compare protein expression with protein phosphorylation data regarding the composition of the PSD proteome obtained from rodent cerebral tissue [11]. It has, therefore, been found that the PSD shows regional differences, especially in terms of protein phosphorylation that is relatively higher in the hippocampus [11]. Moreover, it has been recently reported that microRNAs (miRNAs) precursors can be detected within synaptic fractions tightly associated with the PSD, where they play a role in the direct or indirect regulation of membrane receptors expression [12,13]. Altogether, these findings may reflect regional variations in the molecular mechanisms underlying synaptic plasticity processes in different areas of the brain.
Scaffold molecules at the PSD are major players in the regulation of synaptic plasticity processes. Indeed, by linking the different components of glutamate receptor complexes and by regulating glutamate receptor trafficking, scaffold proteins modulate the signaling cascade starting from membrane receptors and ultimately regulate dendritic structure and function [4,14].
Within the scaffold protein subset, the NMDA receptor and type I metabotropic glutamate receptor (mGluR1/5) scaffold members of the membrane-associated guanylyl kinase (MAGUK) family, the Homer and the ProSAP/Shank (SH3 domain and ankyrin repeat-containing protein) families of proteins are the molecules that have mostly attracted study since the accumulating evidence of their direct involvement in synaptic plasticity processes [4,15].
Proteins containing the PSD-95/disc large/zonula occludens-1 (PDZ) domain are considered a hallmark of the PSD, and the MAGUKs, including PSD-95, SAP102 and PSD-93, comprise three PDZ domains in their N-terminus followed by a src homology-3 (SH3) domain and a guanylate kinase (GK) domain in the C-terminus [16]. PDZ domains are peptide-binding domains, which allow the above-mentioned proteins to interact with a variety of binding partners within the PSD, such as NMDA receptors, as well as cytoplasmic proteins [17]. Moreover, it has been shown that PSD-95 may interact with dopamine and serotonin receptors and regulate their activation state [18,19]. Therefore, MAGUKs participate to the formation of protein complexes within the PSD by assembling in multimers that stabilize membrane receptors and provide a physical link between receptors and intracellular molecules at the crossroad among glutamatergic, dopaminergic, and serotonergic signaling pathways [6,9].
The other well-known family of PSD scaffolds is the ones of the Homers, which is composed by three isoforms in mammals (Homer 1, Homer 2, and Homer 3) and takes part to a variety of biological functions within the PSD [20]. To note, Homer isoforms include two inducible, non-multimerizing splice variants (namely, Homer 1a and Ania-3), which lack the C-terminal domain and are expressed in an immediate-early gene fashion secondary to a variety of neuronal stimuli [20]. Particularly, Homer 1a acts like a dominant negative since it lacks the oligomerization domain and disrupts long Homer-mediated clusters that anchor type I mGluRs to NMDA receptors and bridge mGluRs to their intracellular downstream effectors [21,22]. Therefore, Homers long versus inducible isoforms expression pattern plays a central role in the modulation of the cross-talk between the glutamatergic and different neurotransmitter signaling pathways, in the regulation of intracellular Ca2+ dynamics and, ultimately, in dendritic spine remodeling [20,23].
Finally, the ProSAP/Shank family of proteins is composed by Shank 1, Shank 2, and Shank 3, which are considered key organizing PSD scaffolds implicated in modulating glutamate neurotransmission [14,24]. Particularly, Shank proteins allow the formation of polymeric network complexes that require the assembly of Homer tetramers and have been proposed to build functional platforms for other PSD proteins [25].
Indeed, affinity-purified complexes obtained from PSD fractions have been described to include 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propanoic acid (AMPA) receptor subunits (GluR1, GluR2, GluR3, GluR4), subunits of the NMDA receptor (NR1, NR2A, NR2B), G protein regulators and scaffolds such as PSD-95, Shank 2, Shank 3, and Homers [26].
PSD proteins have been crucially involved also in direct interactions amongst membrane receptors. Indeed, growing evidence has been accumulating demonstrating complex connections between glutamatergic and dopaminergic receptors, which implicate imbricated interactions with PSD structures (see [23] for a review). Lee et al. [27], for instance, have reported direct co-immunoprecipitation of NMDA glutamate and D1 dopamine receptors in both hippocampal and striatal cultures. Moreover, the manipulation of either NMDA or D1 receptor may reciprocally influence each other’s functions [28]. However, the scaffolding protein PSD-95 seems to be crucially required for D1 dopamine receptors in order to modulate NMDA currents [29], as well as PSD-95 has been described to directly regulate NMDA functions by abolishing the NMDA-mediated inhibition of D1 receptors internalization [18].
Interestingly, PSD molecules have been implicated also in the fine modulation of transductional pathways starting at dopamine D3 receptors, a subtype of dopamine receptors which has gained increasing interest because of its role in schizophrenia, drug addiction, and antipsychotics mechanisms of action [30]. Peculiarly, the expression of D3 receptors has been demonstrated to be regulated by Brain-Derived Neurotrophic Factor (BDNF) in the nucleus accumbens during development and adulthood [31], a feature that tightly links these receptors to the developmental pathogenetic hypothesis of psychosis and depression, as well as the selective expression of D3 receptors in proliferative zones of striatal granule cells during embryonic development [32].
At the synaptic level, D3 receptors have been found surprisingly located in asymmetric synapses at the head of dendritic spines [33], differently from D1 and D2 receptors that are diffused all over dendrites in striatum, and this peculiar localization suggests direct interaction with NMDA and AMPA glutamate receptors at postsynaptic sites [34]. Indeed, D3 receptors may bind calcium/calmodulin-dependent protein kinase (CaMKII) in the PSD-enriched nucleus accumbens neurons and the activation of NMDA receptors may stimulate D3 function by increasing calcium-dependent CaMKII activation [35]. The modulation of D3 receptors function by PSD is also suggested by a direct impact of D2/D3 selectively binding antipsychotics, such as amisulpride, on the expression of PSD genes [36,37].
Clinical and preclinical studies have extensively provided evidence of abnormal expression and/or functioning of various PSD proteins in diseases such as schizophrenia, bipolar disorder, and autism [9,38,39,40]. These findings are not surprising considering the master role of the above-mentioned molecules in synaptic plasticity processes that are considered aberrant in neuropsychiatric diseases [41].
Due to the studies conducted so far, showing that PSD molecules are modulated by antipsychotics [37,42,43] and play a key role in behavioral conducts [44,45], these molecules are gaining relevant interest as putative targets of pharmacological strategies. However, there are still potential limitations that may apparently prevent large-scale development of PSD protein-targeted therapeutic devices.
Despite strong genetic evidence [46], the specific role of PSD molecules in the pathophysiology (and putatively in therapeutics) of psychiatric diseases is still elusive. One possible hypothesis is that PSD molecules may concur to synaptic pathology in multiple psychiatric conditions, such as autism [47], schizophrenia [48,49], or mood disorders [50]. According to this view, in schizophrenia post-mortem brain tissue an altered expression of proteins belonging to the PSD fraction it has been observed, leading to the conclusion that, within the PSD, NMDA-interacting, and endocytosis-related proteins contribute to schizophrenia pathophysiology [49]. Moreover, transgenic animal models carrying mutations in the genes coding for PSD molecules exhibit clear behavioral phenotypes relevant to psychopathological conditions in psychiatric diseases [51,52,53,54]. Genetic manipulations of PSD molecules cause dendritic spine defects, which are putatively the basis for behavioral aberrations relevant to psychiatric diseases [55,56]. This increasing body of evidence supports the view that PSD proteins are crucially implicated in aberrant synaptic plasticity, and thereby in high-order cognitive alterations, which are the core of pathophysiology in psychiatric diseases.
Here we review the latest studies regarding the role of PSD molecules in the mechanisms of action of the psychopharmacologic drugs mainly used in the treatment of major psychiatric disorders. Moreover, we will explore possible new avenues in the horizon of “PSD-targeting” therapeutic strategies.

2. Involvement of PSD Molecules in Psychiatric Drugs Mechanisms of Actions

Consistent with the crucial position of postsynaptic proteins at the crossroads of transductional pathways implicated in synaptic plasticity, several studies have demonstrated their central role in the mechanisms of action of drugs currently considered as the mainstay treatment of major psychiatric disorders, such as antipsychotics, antidepressants, and mood stabilizers (Figure 1).

2.1. Antipsychotic Drugs

Since the very early studies on the impact of antipsychotic treatment on the brain it was clear that these drugs may induce ultrastructural changes in both cortical and subcortical glutamatergic synapses with significant differences between first generation (FGA) and second generation antipsychotics (SGA) [57,58,59]. Moreover, early studies by de Bartolomeis’s laboratory team demonstrated that both FGAs and SGAs may directly impact the scaffolding proteins that constitute the architecture of PSD via differentially inducing, in both acute and chronic paradigms, the expression of the immediate-early gene Homer 1a [60,61]. Particularly, the specific perturbation of dopaminergic signaling may lead to concurrently specific differential topographical brain expressions of Homer family PSD genes directly depending on the receptor profile of the antipsychotic [62], thereby suggesting Homer as a molecular marker of glutamatergic impact by antipsychotics. PSD molecules directly linked to glutamate NMDA receptors, such as PDS95, have been demonstrated to be modified by FGAs and SGAs [63]. More recent studies specifically correlated the impact of SGAs on PSD-95 with their ability to modulate serotonergic neurotransmission together with dopaminergic one [64].
The effects of antipsychotics on PSD molecules are so specific that the topographical pattern of PSD genes expression may vary with the dose of the antipsychotic administered: indeed, increasing doses of selected FGAs or SGAs may progressively recruit the expression of crucial PSD genes, such as Zif268, Homer1a, Arc, and c-fos, while gradually impacting selected brain areas [42]. Moreover, the common clinical practice of switching antipsychotic has been demonstrated to specifically perturb PSD molecules depending on the specific switch procedure (especially FGA to SGA, or vice versa) [37].
Therefore, antipsychotics may basically modify the architecture of the synapse through determining rearrangements of a complex calcium-regulated network with the final aim of integrating and routing both dopaminergic and glutamatergic signaling pathways to appropriate nuclear targets, therefore, finally impacting the intrinsic functions of synapses in selected brain areas [23]. Recent researches, indeed, pointed out the essential role of PSD molecules in the morphologic changes of dendritic spines induced by long-term antipsychotic treatment [65]. Moreover, a crucial role of microRNAs interactions with PSD molecules has been suggested in the radical synaptic plasticity rearrangements induced by antipsychotics [66].

2.2. Mood-Stabilizing Drugs

Several studies have demonstrated that mood stabilizing drugs, although very different amongst each other in chemical structure and mechanisms of action (especially lithium vs. valproate), may share a common impact on crucial components of post-receptor transductional pathways, such as the glycogen synthase kinase 3β (GSK3β) or the mitogen-activated protein kinases (MAPKs) [67]. Both lithium and valproate, by acting on those molecules, may control glutamatergic signaling via reducing membrane insertion of AMPA glutamate receptors through the regulation of GluR1 AMPA subunits phosphorylation status [68]. A similar action has been described for NMDA glutamate receptors, whose membrane insertion may be controlled by lithium through a direct action on NR2A phosphorylation and its interaction with PSD95 [69]. The impact of both lithium and valproate on GSK3β has been associated to a long-term increase in hippocampal synapse formation and connections, which could be directly correlated to mood stabilizing effects [70].
More recent studies demonstrated that chronic treatment with both lithium and valproate may affect the expression of genes coding for structural proteins of postsynaptic density, such as Homer 1b/c, Shank and Inositol-1,4,5 trisphosphate receptors (IP3Rs), which all represent a putative connection between glutamatergic and dopaminergic function as a further mood-stabilizing mechanism [71]. Moreover, when added to antipsychotics (such as it frequently occurs in clinical practice), mood stabilizers may induce a differential modulation of PSD molecules as compared to the effects of individual drugs in both cortical and subcortical brain regions [72]. Indeed, a growing body of evidence suggests a direct impact of mood stabilizers on dopaminergic neurotransmission [73], as well as that PSD molecules represents crucial dopamine-glutamate crossroads for the combined actions of mood stabilizers and antipsychotics [74].
Other mood stabilizers, such as carbamazepine and lamotrigine, although not sharing a common action on GSK3β as lithium and valproate, have been demonstrated to impact inositol pathways and MAPK cascades, which also represent core crossroads of dopamine-glutamate postsynaptic interplay [75,76].

2.3. Antidepressant Drugs

A complex dysfunction in synaptic plasticity of specific brain areas, such as the hippocampus and prefrontal cortex, is a well-known pathophysiological mechanism in depression [77]. Human studies have demonstrated that glutamate neurotransmission is impaired in cortical subregions in subjects suffering from major depression, with higher levels of NMDA receptors subunits in frontal cortex and even higher NMDA levels in parietal cortex in suicide completers, as well as reduced levels in dorsolateral prefrontal cortex and higher PSD-95 levels in anterior cingulate [78].
Chronic antidepressant treatment may induce morphological changes in the abovementioned brain areas through the direct modulation of PSD proteins. Indeed, fluoxetine has been demonstrated to increase the expression of hippocampal PSD95 and AMPA receptors subunit GluR1 via a mechanism involving TrkB receptors of BDNF [79]. Changes in both NMDA and AMPA receptors subunits provoked by chronic fluoxetine have been associated with forebrain up-regulation in dendritic spines and formation of mushroom-type spines [80]. Based on those observations regarding glutamate neurotransmission modulation by antidepressants, some studies have demonstrated that also serotonin receptors-modulating antipsychotics, such as lurasidone, may provoke hippocampal PSD proteins modulation and dendritic spines changes similar to that induced by fluoxetine [81]. Additionally, lurasidone has been demonstrated to exert antidepressant properties through a direct modulation of BDNF in prefrontal cortex of animal models of depressive states, thus suggesting a crucial impact of this drug on pathophysiologic neuroplastic mechanisms underlying depression [82,83]. Moreover, the concurrent administration of antipsychotics and SSRI antidepressants may induce synergistic modulation of specific PSD molecules, such as Homer 1a, thereby suggesting a fundamental crosstalk of serotonin and dopamine transductional pathways in the pathophysiology of depressive states [84]. Core molecules related to dopamine signal transduction, such as DARPP-32 have been reported to be significantly modulated by antidepressants, as well as the combination of antipsychotics and antidepressants may synergistically impact synaptic proteins related to energetic metabolism (for a review see: [74]). The essential role of dopamine modulation in depression, as well as the tight imbrication with pathophysiologic mechanisms also involved in schizophrenia, may be confirmed by the fact that dopaminergic antidepressant drugs, such as bupropion, have been demonstrated to be safe and effective in depressive states occurring in schizophrenic patients [85].
The above described glutamatergic postsynaptic mechanisms have been reported to be on the basis of the rapid antidepressant properties displayed by ketamine, an NMDA antagonist. Indeed, ketamine has been demonstrated to induce hippocampal PSD-95 modulation via the TrkB-BDNF pathway similar to those provoked by fluoxetine, but in a more rapid and unstable manner [86]. Moreover, the administration of lithium may potentiate the synaptogenic and antidepressant effects of ketamine by inhibiting GSK3β [87]. Recently, ketamine has been demonstrated to exert its antidepressant effects essentially via its metabolite hydroxynorketamine. Indeed, the R-enantiomer of hydroxynorketamine shows behavioral and biochemical antidepressants effects that seem independent from NMDA receptors’ inhibition, but involve a robust increase in AMPA receptors-mediated excitatory postsynaptic currents [88]. AMPA receptors, in fact, have been crucially correlated to the pathogenesis of both psychosis and mood disorders. Early deletion of AMPA GluR1 subunit may induce striatal hyperdopaminergia and behavioral abnormalities mimicking psychosis [89], as well as AMPA knockout mice exhibit increased learned helplessness, decreased serotonin and norepinephrine, and impaired glutamate neurotransmission, all features modeling depressive phenotypes [90]. However, only early impairment of AMPA function has been demonstrated to induce neuropsychiatric phenotypes, since post-adolescence-induced AMPA ablation results in normal behaviors in animal models [91,92]. These findings suggest that global dysfunctions of glutamatergic signaling that onset during early development are necessary to establish full depressive phenotypes. Indeed, ketamine has been demonstrated to have no effects on juvenile animals, because developmentally mature synapses are required to induce antidepressant responses [93].
Regarding the role of PSD proteins in the mechanisms of action of glutamatergic antidepressant drugs, since the modulation of both the GluN2A and GluN2B subunits of the NMDA receptor has been reported to individually exert antidepressant effects [94], a recent study demonstrated that the impairment of PSD-95 constitutive functions may impair NMDA-GluN2B-mediated antidepressant-like responses [95].
PSD molecules involvement in major neuropsychiatric disorders and their modulation by main psychopharmacologic drugs are summarized in Table 1.

3. Novel Putative Therapeutic Strategies Based on PSD Molecules Modulation

Based on the studies described above, it can be expected that, once the molecular mechanisms implicated in each distinct psychiatric disease would be at least partially unveiled, modulation of PSD molecules will be instrumental at restoring physiological synaptic functioning and, consequently, network connections at micro- and macro-circuit levels. However, as a challenge, the exact brain division, and even the cellular type, where these molecules operate to modulate definite behavioral conducts, and to putatively cause aberrations, has not been fully characterized. Nonetheless, an increasing body of evidence is locating PSD alterations in specific brain sites. In post-mortem brain samples from schizophrenia patients, significant changes in key PSD molecules (i.e., PSD-95, Homer 1a, Homer 1b, Preso) have been demonstrated in multiple brain regions, including the hippocampal CA1 region, the prefrontal cortex, and the olfactory bulb [96]. Exact delivery of PSD-targeting therapeutic agents in brain subdivisions or cell types implicated in disease pathophysiology may be crucial to maximize pharmacological efficacy and/or minimize untoward effects. Despite this field still being in its formative stage, recent novel technological approaches are attempting to overcome the challenges deriving from cell-type restricted drug delivery within the Central Nervous System (CNS), as in the case of the recent advent of nanomedicines, which provide potent tools to implement CNS targeted delivery of active compounds [97]. Great advances are mainly taking place in other biomedical fields, such as oncology or neurology. One such example is multiple sclerosis, where advanced drug delivery of the so-called disease-modifying therapies is under thorough investigation in order to decrease adverse effects, increase drug efficacy, and increase patient compliance through the direct targeting of pathologic cells [98]. Among advanced drug delivery systems, current studies are accounting for nanoparticles, microparticles, fusion antibodies, and liposomal formulations. Additionally, there is increasing efforts to delineate alternative routes of drug administration, such as the nasal route for systemic use, in order to cross the blood-brain banner (BBB) [99]. A recent report has demonstrated that the intranasal administration of a sertraline-conjugated small-interfering RNA (siRNA) was effective in silencing the expression and diminishing the biological function of the serotonin transporter (SERT) and evoked fast antidepressant-like responses in mice [100]. Overall these breakthrough drug delivery technologies are aimed at being applicable to multiple disease treatments in the CNS and may allow to precisely target pharmacological agents to PSD molecules in the cell types where their alterations participate in pathophysiology of psychiatric diseases.
As a third valuable challenge, it has to be mentioned that as PSD molecules share both architectural/functional and signaling roles in the post-synaptic neuron, they are simultaneously recruited in several downstream pathways, often representing sites of trans-activation and intersection among different intracellular cascades. Therefore, PSD molecules have pleiotropic biological roles and participate in several downstream pathways concurrently [101,102]. How to selectively target a distinct PSD protein-operated downstream pathway over the concurrent others is another relevant field of research. However, PSD molecule-targeting may more easily attain a modulation of selected downstream pathways compared to receptor-targeting pharmacological devices, possibly representing one of the major advantage of this novel strategy.
Given all the considerations above, modulation of PSD molecules as a therapeutic strategy in psychiatric diseases may occur either indirectly or directly. Indirect PSD molecule modulation intervenes as a consequence of the interaction of a pharmacological agent with their target non-PSD receptors. Indirect modulation may be regarded as an accessory molecular effect of a drug, which may, theoretically, be either incidental or desired. However, to date, there are no designed pharmacological agents whose primary or secondary desirable molecular effects are to specifically modulate PSD targets. On the other hand, multiple psychotropic pharmacological agents have been demonstrated to incidentally modulate gene and protein expression of PSD molecules [81], as also described in sections above. However, this approach has considerable shortcomings. Indeed, a clear demonstration that this effect is related to antipsychotic efficacy is still lacking. As a second cue, it has been only partially demonstrated that psychotropic agent-mediated modulation of expression of PSD molecules may translate in changes at the protein, functional, and behavioral levels. Despite these considerations, it has to be expected that PSD molecules participate in the biological consequences of psychotropic agent administration. This statement is supported by experimental evidence showing that similar modulations of target PSD molecules are the result of different therapeutic procedures. In a recent report, increased expression of the Homer1a in the medial PFC was associated with inhibition of depressive-like behaviors and was the ultimate molecular step of various antidepressant treatments, including sleep deprivation, up-regulation of adenosine 1 receptor, imipramine, or ketamine administration [103]. Evaluation of the pattern of expression of PSD molecules has also been suggested to provide information on augmentation or association therapeutic strategies. It has been reported that Arc expression is differentially modulated by haloperidol alone, or in association with minocycline, a synthetic second-generation tetracycline that has been proposed as an adjunctive treatment mostly for negative symptoms of schizophrenia [104]. In another study, it has been observed that the molecular changes in targeted PSD molecules are different in relation to the timing and the order in which antipsychotics are given [37]. Overall, these reports suggest that PSD molecules are key actors in the mechanisms of action of psychotropic agents and their modulation may represent one of the ultimate biological steps to trigger pharmacological effects of these drugs. In these terms, PSD molecule modulation may characterize other recently proposed therapeutic agents that act on glutamatergic transmission, such as: agonists at group 2/3 metabotropic glutamate receptors; positive allosteric modulators of type 5 metabotropic glutamate receptors; NMDA receptor modulators; AMPAkines; or glycine transporter inhibitors [2,105,106,107,108,109]. However, even in these cases, putative modulation of PSD molecules should be regarded as a secondary, accessory biological effect, whose actual involvement in these agents’ mechanisms of action is yet to be completely elucidated.
One intriguing novel therapeutic strategy should be represented by direct targeting of PSD molecules. In this case, the relevant challenge scientists should face is the intracerebral and intracellular localization of these molecules, which would constrain novel putative pharmacological agents to face a double barrier, i.e., the blood-brain barrier and the cell membrane. In fact, current agents in neurology and psychiatry are able to cross the blood-brain barrier, due to their high lipophilicity. Only recently technological advance has made it possible to develop pharmacological devices with the aptitude to trespass the neuron cell membrane and interact with protein or genic elements [110]. NA-1 is a recently described PSD-95 small-peptide inhibitor, which prevents PSD-95 interaction with the NR2B subunit of NMDA receptors, thereby uncoupling NMDA receptors from nNOS-mediated downstream neurotoxic signaling pathways [111]. Notably, this uncoupling does not affect NMDA receptor-mediated excitatory neurotransmission in the brain [111]. NA-1 has been previously tested in rat and non-human primate models of transient focal ischemia and stroke [112,113]. Subsequently, this agent has been studied in clinical stroke treatment in humans [114] and is currently undergoing phase III clinical trials.
NA-1 represents a paradigmatic example of a pharmacological agent, which directly modulates PSD molecules for the treatment of neuropsychiatric disease. The possibility to expand the therapeutic use of NA-1 to behavioral diseases appears minimal, since it targets a very restricted downstream pathway. However, this example opens the way to the possibility of designing small molecule inhibitors to interact with other portion of PSD-95, or with other PSD molecules, in order to disrupt the protein-protein interactions and modulate selected downstream pathways implicated in behavioral disease mechanisms.

4. Conclusions

PSD molecules represent crucial crossroads for multiple receptor signaling involved in the mechanisms of action of the most frequently used psychopharmacologic drugs. Their close intermingling receives, elaborates, and converges multiple signals to the appropriate nuclear targets, in order to finely modulate synaptic rearrangements in response to neural activity. However, PSD molecular mechanisms are so sophisticated and complex that their knowledge is only partial at the moment. Further studies will putatively permit the development of “synapse-targeting” psychopharmacotherapeutics, which could finally bypass the pharmacodynamics and pharmacokinetic problems that currently jeopardize a fully-effective psychopharmacologic treatment.

Acknowledgments

We further thank Elisabetta Filomena Buonaguro for mother-tongue English revision of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sheng, M.; Hoogenraad, C.C. The postsynaptic architecture of excitatory synapses: A more quantitative view. Annu. Rev. Biochem. 2007, 76, 823–847. [Google Scholar] [CrossRef] [PubMed]
  2. De Bartolomeis, A.; Sarappa, C.; Magara, S.; Iasevoli, F. Targeting glutamate system for novel antipsychotic approaches: Relevance for residual psychotic symptoms and treatment resistant schizophrenia. Eur. J. Pharmacol. 2012, 682, 1–11. [Google Scholar] [CrossRef] [PubMed]
  3. Gao, C.; Tronson, N.C.; Radulovic, J. Modulation of behavior by scaffolding proteins of the post-synaptic density. Neurobiol. Learn. Mem. 2013, 105, 3–12. [Google Scholar] [CrossRef] [PubMed]
  4. Iasevoli, F.; Tomasetti, C.; de Bartolomeis, A. Scaffolding proteins of the post-synaptic density contribute to synaptic plasticity by regulating receptor localization and distribution: Relevance for neuropsychiatric diseases. Neurochem. Res. 2013, 38, 1–22. [Google Scholar] [CrossRef] [PubMed]
  5. Collins, M.O.; Husi, H.; Yu, L.; Brandon, J.M.; Anderson, C.N.; Blackstock, W.P.; Choudhary, J.S.; Grant, S.G. Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome. J. Neurochem. 2006, 97, 16–23. [Google Scholar] [CrossRef] [PubMed]
  6. Boeckers, T.M. The postsynaptic density. Cell Tissue Res. 2006, 326, 409–422. [Google Scholar] [CrossRef] [PubMed]
  7. Gold, M.G. A frontier in the understanding of synaptic plasticity: Solving the structure of the postsynaptic density. Bioessays 2012, 34, 599–608. [Google Scholar] [CrossRef] [PubMed]
  8. Emes, R.D.; Pocklington, A.J.; Anderson, C.N.; Bayes, A.; Collins, M.O.; Vickers, C.A.; Croning, M.D.; Malik, B.R.; Choudhary, J.S.; Armstrong, J.D.; et al. Evolutionary expansion and anatomical specialization of synapse proteome complexity. Nat. Neurosci. 2008, 11, 799–806. [Google Scholar] [CrossRef] [PubMed]
  9. De Bartolomeis, A.; Buonaguro, E.F.; Iasevoli, F.; Tomasetti, C. The emerging role of dopamine-glutamate interaction and of the postsynaptic density in bipolar disorder pathophysiology: Implications for treatment. J. Psychopharmacol. 2014, 28, 505–526. [Google Scholar] [CrossRef] [PubMed]
  10. Kneussel, M. Postsynaptic scaffold proteins at non-synaptic sites. The role of postsynaptic scaffold proteins in motor-protein-receptor complexes. EMBO Rep. 2005, 6, 22–27. [Google Scholar] [CrossRef] [PubMed]
  11. Trinidad, J.C.; Thalhammer, A.; Specht, C.G.; Lynn, A.J.; Baker, P.R.; Schoepfer, R.; Burlingame, A.L. Quantitative analysis of synaptic phosphorylation and protein expression. Mol. Cell. Proteom. 2008, 7, 684–696. [Google Scholar] [CrossRef] [PubMed]
  12. Wibrand, K.; Panja, D.; Tiron, A.; Ofte, M.L.; Skaftnesmo, K.O.; Lee, C.S.; Pena, J.T.; Tuschl, T.; Bramham, C.R. Differential regulation of mature and precursor microRNA expression by NMDA and metabotropic glutamate receptor activation during LTP in the adult dentate gyrus in vivo. Eur. J. Neurosci. 2010, 31, 636–645. [Google Scholar] [CrossRef] [PubMed]
  13. Lugli, G.; Larson, J.; Demars, M.P.; Smalheiser, N.R. Primary microRNA precursor transcripts are localized at post-synaptic densities in adult mouse forebrain. J. Neurochem. 2012, 123, 459–466. [Google Scholar] [CrossRef] [PubMed]
  14. Vessey, J.P.; Karra, D. More than just synaptic building blocks: Scaffolding proteins of the post-synaptic density regulate dendritic patterning. J. Neurochem. 2007, 102, 324–332. [Google Scholar] [CrossRef] [PubMed]
  15. Bayes, A.; van de Lagemaat, L.N.; Collins, M.O.; Croning, M.D.R.; Whittle, I.R.; Choudhary, J.S.; Grant, S.G.N. Characterization of the proteome, diseases and evolution of the human postsynaptic density. Nat. Neurosci. 2011, 14, 19–21. [Google Scholar] [CrossRef] [PubMed]
  16. Xu, W.F. PSD-95-like membrane associated guanylate kinases (PSD-MAGUKs) and synaptic plasticity. Curr. Opin. Neurobiol. 2011, 21, 306–312. [Google Scholar] [CrossRef] [PubMed]
  17. Kim, E.J.; Sheng, M. PDZ domain proteins of synapses. Nat. Rev. Neurosci. 2004, 5, 771–781. [Google Scholar] [CrossRef] [PubMed]
  18. Zhang, J.P.; Xu, T.X.; Hallett, P.J.; Watanabe, M.; Grant, S.G.N.; Isacson, O.; Yao, W.D. PSD-95 Uncouples Dopamine-Glutamate Interaction in the D-1/PSD-95/NMDA Receptor Complex. J. Neurosci. 2009, 29, 2948–2960. [Google Scholar] [CrossRef] [PubMed]
  19. Zhang, J.; Lewis, S.M.; Kuhlman, B.; Lee, A.L. Supertertiary Structure of the MAGUK Core from PSD-95. Structure 2013, 21, 402–413. [Google Scholar] [CrossRef] [PubMed]
  20. Shiraishi-Yamaguchi, Y.; Furuichi, T. The Homer family proteins. Genome Biol. 2007, 8, 206. [Google Scholar] [CrossRef] [PubMed]
  21. Kammermeier, P. Regulation of mGlur signaling by endogenous homer proteins. Neuropharmacology 2008, 55, 604. [Google Scholar]
  22. Ango, F.; Prezeau, L.; Muller, T.; Tu, J.C.; Xiao, B.; Worley, P.F.; Pin, J.P.; Bockaert, J.; Fagni, L. Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer. Nature 2001, 411, 962–965. [Google Scholar] [CrossRef] [PubMed]
  23. De Bartolomeis, A.; Tomasetti, C. Calcium-dependent networks in dopamine-glutamate interaction: The role of postsynaptic scaffolding proteins. Mol. Neurobiol. 2012, 46, 275–296. [Google Scholar] [CrossRef] [PubMed]
  24. Boeckers, T.M.; Bockmann, J.; Kreutz, M.R.; Gundelfinger, E.D. ProSAP/Shank proteins—A family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease. J. Neurochem. 2002, 81, 903–910. [Google Scholar] [CrossRef] [PubMed]
  25. Hayashi, M.K.; Tang, C.Y.; Verpelli, C.; Narayanan, R.; Stearns, M.H.; Xu, R.M.; Li, H.L.; Sala, C.; Hayashi, Y. The Postsynaptic Density Proteins Homer and Shank Form a Polymeric Network Structure. Cell 2009, 137, 159–171. [Google Scholar] [CrossRef] [PubMed]
  26. Dosemeci, A.; Makusky, A.J.; Jankowska-Stephens, E.; Yang, X.; Slotta, D.J.; Markey, S.P. Composition of the synaptic PSD-95 complex. Mol. Cell. Proteom. 2007, 6, 1749–1760. [Google Scholar] [CrossRef] [PubMed]
  27. Lee, F.J.; Xue, S.; Pei, L.; Vukusic, B.; Chery, N.; Wang, Y.; Wang, Y.T.; Niznik, H.B.; Yu, X.M.; Liu, F. Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell 2002, 111, 219–230. [Google Scholar] [CrossRef]
  28. Lee, F.J.; Liu, F. Direct interactions between NMDA and D1 receptors: A tale of tails. Biochem. Soc. Trans. 2004, 32, 1032–1036. [Google Scholar] [CrossRef] [PubMed]
  29. Gu, W.H.; Yang, S.; Shi, W.X.; Jin, G.Z.; Zhen, X.C. Requirement of PSD-95 for dopamine D1 receptor modulating glutamate NR1a/NR2B receptor function. Acta Pharmacol. Sin. 2007, 28, 756–762. [Google Scholar] [CrossRef] [PubMed]
  30. Sokoloff, P.; Le Foll, B. The dopamine D3 receptor, a quarter century later. Eur. J. Neurosci. 2016, 45, 2–19. [Google Scholar] [CrossRef] [PubMed]
  31. Guillin, O.; Diaz, J.; Carroll, P.; Griffon, N.; Schwartz, J.C.; Sokoloff, P. BDNF controls dopamine D3 receptor expression and triggers behavioural sensitization. Nature 2001, 411, 86–89. [Google Scholar] [CrossRef] [PubMed]
  32. Inta, D.; Cameron, H.A.; Gass, P. New neurons in the adult striatum: From rodents to humans. Trends Neurosci. 2015, 38, 517–523. [Google Scholar] [CrossRef] [PubMed]
  33. Diaz, J.; Pilon, C.; Le Foll, B.; Gros, C.; Triller, A.; Schwartz, J.C.; Sokoloff, P. Dopamine D3 receptors expressed by all mesencephalic dopamine neurons. J. Neurosci. 2000, 20, 8677–8684. [Google Scholar]
  34. Bernard, V.; Bolam, J.P. Subcellular and subsynaptic distribution of the NR1 subunit of the NMDA receptor in the neostriatum and globus pallidus of the rat: Co-Localization at synapses with the GluR2/3 subunit of the AMPA receptor. Eur. J. Neurosci. 1998, 10, 3721–3736. [Google Scholar] [CrossRef] [PubMed]
  35. Liu, X.Y.; Mao, L.M.; Zhang, G.C.; Papasian, C.J.; Fibuch, E.E.; Lan, H.X.; Zhou, H.F.; Xu, M.; Wang, J.Q. Activity-dependent modulation of limbic dopamine D3 receptors by CaMKII. Neuron 2009, 61, 425–438. [Google Scholar] [CrossRef] [PubMed]
  36. De Bartolomeis, A.; Marmo, F.; Buonaguro, E.F.; Rossi, R.; Tomasetti, C.; Iasevoli, F. Imaging brain gene expression profiles by antipsychotics: Region-specific action of amisulpride on postsynaptic density transcripts compared to haloperidol. Eur. Neuropsychopharmacol. 2013, 23, 1516–1529. [Google Scholar] [CrossRef] [PubMed]
  37. De Bartolomeis, A.; Marmo, F.; Buonaguro, E.F.; Latte, G.; Tomasetti, C.; Iasevoli, F. Switching antipsychotics: Imaging the differential effect on the topography of postsynaptic density transcripts in antipsychotic-naive vs. antipsychotic-exposed rats. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2016, 70, 24–38. [Google Scholar] [CrossRef] [PubMed]
  38. Grabrucker, A.M. A Role for Synaptic Zinc in ProSAP/Shank PSD Scaffold Malformation in Autism Spectrum Disorders. Dev. Neurobiol. 2014, 74, 136–146. [Google Scholar] [CrossRef] [PubMed]
  39. Grabrucker, S.; Jannetti, L.; Eckert, M.; Gaub, S.; Chhabra, R.; Pfaender, S.; Mangus, K.; Reddy, P.P.; Rankovic, V.; Schmeisser, M.J.; et al. Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders. Brain 2014, 137, 137–152. [Google Scholar] [CrossRef] [PubMed]
  40. Grabrucker, S.; Proepper, C.; Mangus, K.; Eckert, M.; Chhabra, R.; Schmeisser, M.J.; Boeckers, T.M.; Grabrucker, A.M. The PSD protein ProSAP2/Shank3 displays synapto-nuclear shuttling which is deregulated in a schizophrenia-associated mutation. Exp. Neurol. 2014, 253, 126–137. [Google Scholar] [CrossRef] [PubMed]
  41. Grant, S.G.N. Synaptopathies: Diseases of the synaptome. Curr.Opin. Neurobiol. 2012, 22, 522–529. [Google Scholar] [CrossRef] [PubMed]
  42. De Bartolomeis, A.; Iasevoli, F.; Marmo, F.; Buonaguro, E.F.; Eramo, A.; Rossi, R.; Avvisati, L.; Latte, G.; Tomasetti, C. Progressive recruitment of cortical and striatal regions by inducible postsynaptic density transcripts after increasing doses of antipsychotics with different receptor profiles: Insights for psychosis treatment. Eur. Neuropsychopharmacol. 2015, 25, 566–582. [Google Scholar] [CrossRef] [PubMed]
  43. Iasevoli, F.; Tomasetti, C.; Marmo, F.; Bravi, D.; Arnt, J.; de Bartolomeis, A. Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole. Psychopharmacology 2010, 212, 329–344. [Google Scholar] [CrossRef] [PubMed]
  44. Peykov, S.; Berkel, S.; Schoen, M.; Weiss, K.; Degenhardt, F.; Strohmaier, J.; Weiss, B.; Proepper, C.; Schratt, G.; Nothen, M.M.; et al. Identification and functional characterization of rare SHANK2 variants in schizophrenia. Mol. Psychiatry 2015, 20, 1489–1498. [Google Scholar] [CrossRef] [PubMed]
  45. Zhang, W.C.; Wu, J.; Ward, M.D.; Yang, S.G.; Chuang, Y.A.; Xiao, M.F.; Li, R.J.; Leahy, D.J.; Worley, P.F. Structural basis of arc binding to synaptic proteins: Implications for cognitive disease. Neuron 2015, 86, 490–500. [Google Scholar] [CrossRef] [PubMed]
  46. Xing, J.R.; Kimura, H.; Wang, C.Y.; Ishizuka, K.; Kushima, I.; Arioka, Y.; Yoshimi, A.; Nakamura, Y.; Shiino, T.; Oya-Ito, T.; et al. Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders. Sci. Rep. 2016, 6, 27491. [Google Scholar] [CrossRef] [PubMed]
  47. Leblond, C.S.; Nava, C.; Polge, A.; Gauthier, J.; Huguet, G.; Lumbroso, S.; Giuliano, F.; Stordeur, C.; Depienne, C.; Mouzaf, K.; et al. Meta-analysis of SHANK mutations in autism spectrum disorders: A gradient of severity in cognitive impairments. PLoS Genet. 2014, 10, e1004580. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Matosin, N.; Green, M.J.; Andrews, J.L.; Newell, K.A.; Fernandez-Enright, F. Possibility of a sex-specific role for a genetic variant in FRMPD4 in schizophrenia, but not cognitive function. Neuroreport 2016, 27, 33–38. [Google Scholar] [CrossRef] [PubMed]
  49. Hall, J.; Trent, S.; Thomas, K.L.; O'Donovan, M.C.; Owen, M.J. Genetic risk for schizophrenia: Convergence on synaptic pathways involved in plasticity. Biol. Psychiatry 2015, 77, 52–58. [Google Scholar] [CrossRef] [PubMed]
  50. Karolewicz, B.; Szebeni, K.; Gilmore, T.; Maciag, D.; Stockmeier, C.A.; Ordway, G.A. Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression. Int. J. Neuropsychopharmacol. 2009, 12, 143–153. [Google Scholar] [CrossRef] [PubMed]
  51. Krueger-Burg, D.; Winkler, D.; Mitkovski, M.; Daher, F.; Ronnenberg, A.; Schluter, O.M.; Dere, E.; Ehrenreich, H. The socioBox: A novel paradigm to assess complex social recognition in male mice. Front. Behav. Neurosci. 2016, 10, 151. [Google Scholar] [CrossRef] [PubMed]
  52. De Bartolomeis, A.; Errico, F.; Aceto, G.; Tomasetti, C.; Usiello, A.; Iasevoli, F. d-aspartate dysregulation in Ddo-/- mice modulates phencyclidine-induced gene expression changes of postsynaptic density molecules in cortex and striatum. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2015, 62, 35–43. [Google Scholar] [CrossRef] [PubMed]
  53. Zhang, J.P.; Saur, T.; Duke, A.N.; Grant, S.G.N.; Platt, D.M.; Rowlett, J.K.; Isacson, O.; Yao, W.D. Motor impairments, striatal degeneration, and altered dopamine-glutamate interplay in mice lacking PSD-95. J. Neurogenet. 2014, 28, 98–111. [Google Scholar] [CrossRef] [PubMed]
  54. Jiang, Y.H.; Ehlers, M.D. Modeling Autism by SHANK Gene Mutations in Mice. Neuron 2013, 78, 8–27. [Google Scholar] [CrossRef]
  55. Manago, F.; Mereu, M.; Mastwal, S.; Mastrogiacomo, R.; Scheggia, D.; Emanuele, M.; de Luca, M.A.; Weinberger, D.R.; Wang, K.H.; Papaleo, F. Genetic disruption of Arc/Arg3.1 in mice causes alterations in dopamine and neurobehavioral phenotypes related to schizophrenia. Cell Rep. 2016, 16, 2116–2128. [Google Scholar] [CrossRef] [PubMed]
  56. Fossati, G.; Morini, R.; Corradini, I.; Antonucci, F.; Trepte, P.; Edry, E.; Sharma, V.; Papale, A.; Pozzi, D.; Defilippi, P.; et al. Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis. Cell Death Differ. 2015, 22, 1425–1436. [Google Scholar] [CrossRef] [PubMed]
  57. Meshul, C.K.; Tan, S.E. Haloperidol-induced morphological alterations are associated with changes in calcium/calmodulin kinase II activity and glutamate immunoreactivity. Synapse 1994, 18, 205–217. [Google Scholar] [CrossRef] [PubMed]
  58. Meshul, C.K.; Stallbaumer, R.K.; Taylor, B.; Janowsky, A. Haloperidol-induced morphological changes in striatum are associated with glutamate synapses. Brain Res. 1994, 648, 181–195. [Google Scholar] [CrossRef]
  59. Vincent, S.L.; McSparren, J.; Wang, R.Y.; Benes, F.M. Evidence for ultrastructural changes in cortical axodendritic synapses following long-term treatment with haloperidol or clozapine. Neuropsychopharmacology 1991, 5, 147–155. [Google Scholar] [PubMed]
  60. Polese, D.; de Serpis, A.A.; Ambesi-Impiombato, A.; Muscettola, G.; de Bartolomeis, A. Homer 1a gene expression modulation by antipsychotic drugs: Involvement of the glutamate metabotropic system and effects of D-cycloserine. Neuropsychopharmacology 2002, 27, 906–913. [Google Scholar] [CrossRef]
  61. De Bartolomeis, A.; Aloj, L.; Ambesi-Impiombato, A.; Bravi, D.; Caraco, C.; Muscettola, G.; Barone, P. Acute administration of antipsychotics modulates Homer striatal gene expression differentially. Brain Res. Mol. Brain Res. 2002, 98, 124–129. [Google Scholar] [CrossRef]
  62. Tomasetti, C.; Dellaversano, C.; Iasevoli, F.; de Bartolomeis, A. Homer splice variants modulation within cortico-subcortical regions by dopamine D2 antagonists, a partial agonist, and an indirect agonist: Implication for glutamatergic postsynaptic density in antipsychotics action. Neuroscience 2007, 150, 144–158. [Google Scholar] [CrossRef] [PubMed]
  63. Fumagalli, F.; Frasca, A.; Racagni, G.; Riva, M.A. Dynamic regulation of glutamatergic postsynaptic activity in rat prefrontal cortex by repeated administration of antipsychotic drugs. Mol. Pharmacol. 2008, 73, 1484–1490. [Google Scholar] [CrossRef] [PubMed]
  64. Abbas, A.I.; Yadav, P.N.; Yao, W.D.; Arbuckle, M.I.; Grant, S.G.; Caron, M.G.; Roth, B.L. PSD-95 is essential for hallucinogen and atypical antipsychotic drug actions at serotonin receptors. J. Neurosci. 2009, 29, 7124–7136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. De Bartolomeis, A.; Latte, G.; Tomasetti, C.; Iasevoli, F. Glutamatergic postsynaptic density protein dysfunctions in synaptic plasticity and dendritic spines morphology: Relevance to schizophrenia and other behavioral disorders pathophysiology, and implications for novel therapeutic approaches. Mol. Neurobiol. 2014, 49, 484–511. [Google Scholar] [CrossRef] [PubMed]
  66. De Bartolomeis, A.; Iasevoli, F.; Tomasetti, C.; Buonaguro, E.F. MicroRNAs in Schizophrenia: Implications for synaptic plasticity and dopamine-glutamate interaction at the postsynaptic density. New avenues for antipsychotic treatment under a theranostic perspective. Mol. Neurobiol. 2015, 52, 1771–1790. [Google Scholar] [CrossRef] [PubMed]
  67. Bachmann, R.F.; Schloesser, R.J.; Gould, T.D.; Manji, H.K. Mood stabilizers target cellular plasticity and resilience cascades: Implications for the development of novel therapeutics. Mol. Neurobiol. 2005, 32, 173–202. [Google Scholar] [CrossRef]
  68. Du, J.; Quiroz, J.; Yuan, P.; Zarate, C.; Manji, H.K. Bipolar disorder: Involvement of signaling cascades and AMPA receptor trafficking at synapses. Neuron Glia Biol. 2004, 1, 231–243. [Google Scholar] [CrossRef] [PubMed]
  69. Ma, J.; Zhang, G.Y. Lithium reduced N-methyl-d-aspartate receptor subunit 2A tyrosine phosphorylation and its interactions with Src and Fyn mediated by PSD-95 in rat hippocampus following cerebral ischemia. Neurosci. Lett. 2003, 348, 185–189. [Google Scholar] [CrossRef]
  70. Kim, H.J.; Thayer, S.A. Lithium increases synapse formation between hippocampal neurons by depleting phosphoinositides. Mol. Pharmacol. 2009, 75, 1021–1030. [Google Scholar] [CrossRef] [PubMed]
  71. De Bartolomeis, A.; Tomasetti, C.; Cicale, M.; Yuan, P.X.; Manji, H.K. Chronic treatment with lithium or valproate modulates the expression of Homer1b/c and its related genes Shank and Inositol 1,4,5-trisphosphate receptor. Eur. Neuropsychopharmacol. 2012, 22, 527–535. [Google Scholar] [CrossRef] [PubMed]
  72. Tomasetti, C.; Dell'Aversano, C.; Iasevoli, F.; Marmo, F.; de Bartolomeis, A. The acute and chronic effects of combined antipsychotic-mood stabilizing treatment on the expression of cortical and striatal postsynaptic density genes. Prog. Neuropsychopharmacol. Biol. Psychiatry 2011, 35, 184–197. [Google Scholar] [CrossRef] [PubMed]
  73. Beaulieu, J.M. Converging evidence for regulation of dopamine neurotransmission by lithium: An editorial highlight for ‘chronic lithium treatment rectifies maladaptive dopamine release in the nucleus accumbens’. J. Neurochem. 2016, 139, 520–522. [Google Scholar] [CrossRef] [PubMed]
  74. De Bartolomeis, A.; Avvisati, L.; Iasevoli, F.; Tomasetti, C. Intracellular pathways of antipsychotic combined therapies: Implication for psychiatric disorders treatment. Eur. J. Pharmacol. 2013, 718, 502–523. [Google Scholar] [CrossRef] [PubMed]
  75. Quiroz, J.A.; Singh, J.; Gould, T.D.; Denicoff, K.D.; Zarate, C.A.; Manji, H.K. Emerging experimental therapeutics for bipolar disorder: Clues from the molecular pathophysiology. Mol. Psychiatry 2004, 9, 756–776. [Google Scholar] [CrossRef] [PubMed]
  76. Gould, T.D.; Quiroz, J.A.; Singh, J.; Zarate, C.A.; Manji, H.K. Emerging experimental therapeutics for bipolar disorder: Insights from the molecular and cellular actions of current mood stabilizers. Mol. Psychiatry 2004, 9, 734–755. [Google Scholar] [CrossRef] [PubMed]
  77. Qiao, H.; Li, M.X.; Xu, C.; Chen, H.B.; An, S.C.; Ma, X.M. Dendritic Spines in Depression: What We Learned from Animal Models. Neural Plast. 2016, 2016, 8056370. [Google Scholar] [CrossRef] [PubMed]
  78. Dean, B.; Gibbons, A.S.; Boer, S.; Uezato, A.; Meador-Woodruff, J.; Scarr, E.; McCullumsmith, R.E. Changes in cortical N-methyl-d-aspartate receptors and post-synaptic density protein 95 in schizophrenia, mood disorders and suicide. Aust. N. Z. J. Psychiatry 2016, 50, 275–283. [Google Scholar] [CrossRef] [PubMed]
  79. O’Leary, O.F.; Wu, X.; Castren, E. Chronic fluoxetine treatment increases expression of synaptic proteins in the hippocampus of the ovariectomized rat: Role of BDNF signalling. Psychoneuroendocrinology 2009, 34, 367–381. [Google Scholar] [CrossRef] [PubMed]
  80. Ampuero, E.; Rubio, F.J.; Falcon, R.; Sandoval, M.; Diaz-Veliz, G.; Gonzalez, R.E.; Earle, N.; Dagnino-Subiabre, A.; Aboitiz, F.; Orrego, F.; et al. Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex. Neuroscience 2010, 169, 98–108. [Google Scholar] [CrossRef] [PubMed]
  81. Stan, T.L.; Sousa, V.C.; Zhang, X.; Ono, M.; Svenningsson, P. Lurasidone and fluoxetine reduce novelty-induced hypophagia and NMDA receptor subunit and PSD-95 expression in mouse brain. Eur. Neuropsychopharmacol. 2015, 25, 1714–1722. [Google Scholar] [CrossRef] [PubMed]
  82. Luoni, A.; Macchi, F.; Papp, M.; Molteni, R.; Riva, M.A. Lurasidone exerts antidepressant properties in the chronic mild stress model through the regulation of synaptic and neuroplastic mechanisms in the rat prefrontal cortex. Int. J. Neuropsychopharmacol. 2014, 18. [Google Scholar] [CrossRef] [PubMed]
  83. Luoni, A.; Berry, A.; Calabrese, F.; Capoccia, S.; Bellisario, V.; Gass, P.; Cirulli, F.; Riva, M.A. Delayed BDNF alterations in the prefrontal cortex of rats exposed to prenatal stress: Preventive effect of lurasidone treatment during adolescence. Eur. Neuropsychopharmacol. 2014, 24, 986–995. [Google Scholar] [CrossRef] [PubMed]
  84. Dell'aversano, C.; Tomasetti, C.; Iasevoli, F.; de Bartolomeis, A. Antipsychotic and antidepressant co-treatment: Effects on transcripts of inducible postsynaptic density genes possibly implicated in behavioural disorders. Brain Res. Bull. 2009, 79, 123–129. [Google Scholar] [CrossRef] [PubMed]
  85. Englisch, S.; Inta, D.; Eer, A.; Zink, M. Bupropion for depression in schizophrenia. Clin. Neuropharmacol. 2010, 33, 257–259. [Google Scholar] [CrossRef] [PubMed]
  86. Liu, W.X.; Wang, J.; Xie, Z.M.; Xu, N.; Zhang, G.F.; Jia, M.; Zhou, Z.Q.; Hashimoto, K.; Yang, J.J. Regulation of glutamate transporter 1 via BDNF-TrkB signaling plays a role in the anti-apoptotic and antidepressant effects of ketamine in chronic unpredictable stress model of depression. Psychopharmacology 2016, 233, 405–415. [Google Scholar] [CrossRef] [PubMed]
  87. Liu, R.J.; Fuchikami, M.; Dwyer, J.M.; Lepack, A.E.; Duman, R.S.; Aghajanian, G.K. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology 2013, 38, 2268–2277. [Google Scholar] [CrossRef] [PubMed]
  88. Zanos, P.; Moaddel, R.; Morris, P.J.; Georgiou, P.; Fischell, J.; Elmer, G.I.; Alkondon, M.; Yuan, P.; Pribut, H.J.; Singh, N.S.; et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016, 533, 481–486. [Google Scholar] [CrossRef] [PubMed]
  89. Wiedholz, L.M.; Owens, W.A.; Horton, R.E.; Feyder, M.; Karlsson, R.M.; Hefner, K.; Sprengel, R.; Celikel, T.; Daws, L.C.; Holmes, A. Mice lacking the AMPA GluR1 receptor exhibit striatal hyperdopaminergia and “schizophrenia-related” behaviors. Mol. Psychiatry 2008, 13, 631–640. [Google Scholar] [CrossRef] [PubMed]
  90. Chourbaji, S.; Vogt, M.A.; Fumagalli, F.; Sohr, R.; Frasca, A.; Brandwein, C.; Hortnagl, H.; Riva, M.A.; Sprengel, R.; Gass, P. AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression. FASEB J. 2008, 22, 3129–3134. [Google Scholar] [CrossRef] [PubMed]
  91. Inta, D.; Vogt, M.A.; Elkin, H.; Weber, T.; Lima-Ojeda, J.M.; Schneider, M.; Luoni, A.; Riva, M.A.; Gertz, K.; Hellmann-Regen, J.; et al. Phenotype of mice with inducible ablation of GluA1 AMPA receptors during late adolescence: Relevance for mental disorders. Hippocampus 2014, 24, 424–435. [Google Scholar] [CrossRef] [PubMed]
  92. Vogt, M.A.; Elkin, H.; Pfeiffer, N.; Sprengel, R.; Gass, P.; Inta, D. Impact of adolescent GluA1 AMPA receptor ablation in forebrain excitatory neurons on behavioural correlates of mood disorders. Eur. Arch. Psychiatry Clin. Neurosci. 2014, 264, 625–629. [Google Scholar] [CrossRef] [PubMed]
  93. Nosyreva, E.; Autry, A.E.; Kavalali, E.T.; Monteggia, L.M. Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade. Front. Mol. Neurosci. 2014, 7, 94. [Google Scholar] [CrossRef] [PubMed]
  94. Jimenez-Sanchez, L.; Campa, L.; Auberson, Y.P.; Adell, A. The role of GluN2A and GluN2B subunits on the effects of NMDA receptor antagonists in modeling schizophrenia and treating refractory depression. Neuropsychopharmacology 2014, 39, 2673–2680. [Google Scholar] [CrossRef] [PubMed]
  95. Kiselycznyk, C.; Jury, N.J.; Halladay, L.R.; Nakazawa, K.; Mishina, M.; Sprengel, R.; Grant, S.G.; Svenningsson, P.; Holmes, A. NMDA receptor subunits and associated signaling molecules mediating antidepressant-related effects of NMDA-GluN2B antagonism. Behav. Brain Res. 2015, 287, 89–95. [Google Scholar] [CrossRef] [PubMed]
  96. Egbujo, C.N.; Sinclair, D.; Borgmann-Winter, K.E.; Arnold, S.E.; Turetsky, B.I.; Hahn, C.G. Molecular evidence for decreased synaptic efficacy in the postmortem olfactory bulb of individuals with schizophrenia. Schizophr. Res. 2015, 168, 554–562. [Google Scholar] [CrossRef] [PubMed]
  97. Grabrucker, A.M.; Ruozi, B.; Belletti, D.; Pederzoli, F.; Forni, F.; Vandelli, M.A.; Tosi, G. Nanoparticle transport across the blood brain barrier. Tissue Barriers 2016, 4, e1153568. [Google Scholar] [CrossRef] [PubMed]
  98. Tabansky, I.; Messina, M.D.; Bangeranye, C.; Goldstein, J.; Blitz-Shabbir, K.M.; Machado, S.; Jeganathan, V.; Wright, P.; Najjar, S.; Cao, Y.H.; et al. Advancing drug delivery systems for the treatment of multiple sclerosis. Immunol. Res. 2015, 63, 58–69. [Google Scholar] [CrossRef] [PubMed]
  99. Ali, J.; Ali, M.; Baboota, S.; Sahni, J.K.; Ramassamy, C.; Dao, L.; Bhavna. Potential of nanoparticulate drug delivery systems by intranasal administration. Curr. Pharm. Des. 2010, 16, 1644–1653. [Google Scholar] [CrossRef] [PubMed]
  100. Ferres-Coy, A.; Galofre, M.; Pilar-Cuellar, F.; Vidal, R.; Paz, V.; Ruiz-Bronchal, E.; Campa, L.; Pazos, A.; Caso, J.R.; Leza, J.C.; et al. Therapeutic antidepressant potential of a conjugated siRNA silencing the serotonin transporter after intranasal administration. Mol. Psychiatry 2016, 21, 328–338. [Google Scholar] [CrossRef] [PubMed]
  101. Yoshii, A.; Constantine-Paton, M. Postsynaptic localization of PSD-95 is regulated by all three pathways downstream of TrkB signaling. Front. Synaptic Neurosci. 2014, 6. [Google Scholar] [CrossRef] [PubMed]
  102. Willard, S.; Koochekpour, S. Glutamate, glutamate receptors, and downstream signaling pathways. Int. J. Biol. Sci. 2013, 9, 948–959. [Google Scholar] [CrossRef] [PubMed]
  103. Serchov, T.; Clement, H.W.; Schwarz, M.K.; Iasevoli, F.; Tosh, D.K.; Idzko, M.; Jacobson, K.A.; de Bartolomeis, A.; Normann, C.; Biber, K.; et al. Increased signaling via adenosine A(1) Receptors, sleep deprivation, imipramine, and ketamine inhibit depressive-like behavior via induction of Homer1a. Neuron 2015, 87, 549–562. [Google Scholar] [CrossRef] [PubMed]
  104. Buonaguro, E.F.; Tomasetti, C.; Chiodini, P.; Marmo, F.; Latte, G.; Rossi, R.; Avvisati, L.; Iasevoli, F.; de Bartolomeis, A. Postsynaptic density protein transcripts are differentially modulated by minocycline alone or in add-on to haloperidol: Implications for treatment resistant schizophrenia. J. Psychopharmacol. 2016. [Google Scholar] [CrossRef] [PubMed]
  105. Fell, M.J.; McKinzie, D.L.; Monn, J.A.; Svensson, K.A. Group II metabotropic glutamate receptor agonists and positive allosteric modulators as novel treatments for schizophrenia. Neuropharmacology 2012, 62, 1473–1483. [Google Scholar] [CrossRef] [PubMed]
  106. Balu, D.T.; Li, Y.; Takagi, S.; Presti, K.T.; Ramikie, T.S.; Rook, J.M.; Jones, C.K.; Lindsley, C.W.; Conn, P.J.; Bolshakov, V.Y.; et al. An mGlu(5)-Positive Allosteric Modulator Rescues the Neuroplasticity Deficits in a Genetic Model of NMDA Receptor Hypofunction in Schizophrenia. Neuropsychopharmacology 2016, 41, 2052–2061. [Google Scholar] [CrossRef] [PubMed]
  107. Iasevoli, F.; Buonaguro, E.F.; Sarappa, C.; Marmo, F.; Latte, G.; Rossi, R.; Eramo, A.; Tomasetti, C.; de Bartolomeis, A. Regulation of postsynaptic plasticity genes’ expression and topography by sustained dopamine perturbation and modulation by acute memantine: Relevance to schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2014, 54, 299–314. [Google Scholar] [CrossRef] [PubMed]
  108. Goff, D.C.; Lamberti, J.S.; Leon, A.C.; Green, M.F.; Miller, A.L.; Patel, J.; Manschreck, T.; Freudenreich, O.; Johnson, S.A. A placebo-controlled add-on trial of the Ampakine, CX516, for cognitive deficits in schizophrenia. Neuropsychopharmacology 2008, 33, 465–472. [Google Scholar] [CrossRef] [PubMed]
  109. Strzelecki, D.; Kaluzynska, O.; Szyburska, J.; Wysokinski, A. MMP-9 Serum Levels in Schizophrenic Patients during Treatment Augmentation with Sarcosine (Results of the PULSAR Study). Int. J. Mol. Sci. 2016, 17, 1075. [Google Scholar] [CrossRef] [PubMed]
  110. Kwon, E.J.; Skalak, M.; Lo Bu, R.; Bhatia, S.N. Neuron-Targeted Nanoparticle for siRNA Delivery to Traumatic Brain Injuries. ACS Nano 2016, 10, 7926–7933. [Google Scholar] [CrossRef] [PubMed]
  111. Aarts, M.; Liu, Y.T.; Liu, L.D.; Besshoh, S.; Arundine, M.; Gurd, J.W.; Wang, Y.T.; Salter, M.W.; Tymianski, M. Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions. Science 2002, 298, 846–850. [Google Scholar] [CrossRef] [PubMed]
  112. Sun, H.S.; Doucette, T.A.; Liu, Y.T.; Fang, Y.; Teves, L.; Aarts, M.; Ryan, C.L.; Bernard, P.B.; Lau, A.; Forder, J.P.; et al. Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke 2008, 39, 2544–2553. [Google Scholar] [CrossRef] [PubMed]
  113. Cook, D.J.; Teves, L.; Tymianski, M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 2012, 483, 213–217. [Google Scholar] [CrossRef] [PubMed]
  114. Hill, M.D.; Martin, R.H.; Mikulis, D.; Wong, J.H.; Silver, F.L.; Terbrugge, K.G.; Milot, G.; Clark, W.M.; MacDonald, R.L.; Kelly, M.E.; et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): A phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2012, 11, 942–950. [Google Scholar] [CrossRef]
  115. Norton, N.; Williams, H.J.; Williams, N.M.; Spurlock, G.; Zammit, S.; Jones, G.; Jones, S.; Owen, R.; O’Donovan, M.C.; Owen, M.J. Mutation screening of the Homer gene family and association analysis in schizophrenia. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 2003, 120B, 18–21. [Google Scholar] [CrossRef] [PubMed]
  116. Szumlinski, K.K.; Lominac, K.D.; Kleschen, M.J.; Oleson, E.B.; Dehoff, M.H.; Schwarz, M.K.; Seeburg, P.H.; Worley, P.F.; Kalivas, P.W. Behavioral and neurochemical phenotyping of Homer1 mutant mice: Possible relevance to schizophrenia. Genes Brain Behav. 2005, 4, 273–288. [Google Scholar] [CrossRef] [PubMed]
  117. Spellmann, I.; Rujescu, D.; Musil, R.; Mayr, A.; Giegling, I.; Genius, J.; Zill, P.; Dehning, S.; Opgen-Rhein, M.; Cerovecki, A.; et al. Homer-1 polymorphisms are associated with psychopathology and response to treatment in schizophrenic patients. J. Psychiatr. Res. 2011, 45, 234–241. [Google Scholar] [CrossRef] [PubMed]
  118. Iasevoli, F.; Tomasetti, C.; Buonaguro, E.F.; de Bartolomeis, A. The Glutamatergic Aspects of Schizophrenia Molecular Pathophysiology: Role of the Postsynaptic Density, and Implications for Treatment. Curr. Neuropharmacol. 2014, 12, 219–238. [Google Scholar] [CrossRef] [PubMed]
  119. Rietschel, M.; Mattheisen, M.; Frank, J.; Treutlein, J.; Degenhardt, F.; Breuer, R.; Steffens, M.; Mier, D.; Esslinger, C.; Walter, H.; et al. Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression. Biol. Psychiatry 2010, 68, 578–585. [Google Scholar] [CrossRef] [PubMed]
  120. Grinevich, V.; Seeburg, P.H.; Schwarz, M.K.; Jezova, D. Homer 1—A new player linking the hypothalamic-pituitary-adrenal axis activity to depression and anxiety. Endocr. Regul. 2012, 46, 153–159. [Google Scholar] [CrossRef] [PubMed]
  121. Zhang, G.C.; Mao, L.M.; Liu, X.Y.; Parelkar, N.K.; Arora, A.; Yang, L.; Hains, M.; Fibuch, E.E.; Wang, J.Q. In vivo regulation of Homer1a expression in the striatum by cocaine. Mol. Pharmacol. 2007, 71, 1148–1158. [Google Scholar] [CrossRef] [PubMed]
  122. Rezvani, K.; Teng, Y.; Shim, D.; de Biasi, M. Nicotine regulates multiple synaptic proteins by inhibiting proteasomal activity. J. Neurosci. 2007, 27, 10508–10519. [Google Scholar] [CrossRef] [PubMed]
  123. Dietrich, J.B.; Arpin-Bott, M.P.; Kao, D.; Dirrig-Grosch, S.; Aunis, D.; Zwiller, J. Cocaine induces the expression of homer 1b/c, homer 3a/b, and hsp 27 proteins in rat cerebellum. Synapse 2007, 61, 587–594. [Google Scholar] [CrossRef] [PubMed]
  124. Hashimoto, K.; Nakahara, T.; Yamada, H.; Hirano, M.; Kuroki, T.; Kanba, S. A neurotoxic dose of methamphetamine induces gene expression of Homer 1a, but not Homer 1b or 1c, in the striatum and nucleus accumbens. Neurochem. Int. 2007, 51, 227–232. [Google Scholar] [CrossRef] [PubMed]
  125. Kane, J.K.; Hwang, Y.; Konu, O.; Loughlin, S.E.; Leslie, F.M.; Li, M.D. Regulation of Homer and group I metabotropic glutamate receptors by nicotine. Eur. J. Neurosci. 2005, 21, 1145–1154. [Google Scholar] [CrossRef] [PubMed]
  126. Lominac, K.D.; Oleson, E.B.; Pava, M.; Klugmann, M.; Schwarz, M.K.; Seeburg, P.H.; During, M.J.; Worley, P.F.; Kalivas, P.W.; Szumlinski, K.K. Distinct roles for different Homer1 isoforms in behaviors and associated prefrontal cortex function. J. Neurosci. 2005, 25, 11586–11594. [Google Scholar] [CrossRef] [PubMed]
  127. Ben-Shahar, O.; Obara, I.; Ary, A.W.; Ma, N.; Mangiardi, M.A.; Medina, R.L.; Szumlinski, K.K. Extended daily access to cocaine results in distinct alterations in Homer 1b/c and NMDA receptor subunit expression within the medial prefrontal cortex. Synapse 2009, 63, 598–609. [Google Scholar] [CrossRef] [PubMed]
  128. Knackstedt, L.A.; Moussawi, K.; Lalumiere, R.; Schwendt, M.; Klugmann, M.; Kalivas, P.W. Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking. J. Neurosci. 2010, 30, 7984–7992. [Google Scholar] [CrossRef] [PubMed]
  129. Tappe, A.; Klugmann, M.; Luo, C.; Hirlinger, D.; Agarwal, N.; Benrath, J.; Ehrengruber, M.U.; During, M.J.; Kuner, R. Synaptic scaffolding protein Homer1a protects against chronic inflammatory pain. Nat. Med. 2006, 12, 677–681. [Google Scholar] [CrossRef] [PubMed]
  130. Yao, Y.X.; Jiang, Z.; Zhao, Z.Q. Knockdown of synaptic scaffolding protein Homer 1b/c attenuates secondary hyperalgesia induced by complete Freund’s adjuvant in rats. Anesth. Analg. 2011, 113, 1501–1508. [Google Scholar] [CrossRef] [PubMed]
  131. Giuffrida, R.; Musumeci, S.; D’Antoni, S.; Bonaccorso, C.M.; Giuffrida-Stella, A.M.; Oostra, B.A.; Catania, M.V. A reduced number of metabotropic glutamate subtype 5 receptors are associated with constitutive homer proteins in a mouse model of fragile X syndrome. J. Neurosci. 2005, 25, 8908–8916. [Google Scholar] [CrossRef] [PubMed]
  132. Roselli, F.; Hutzler, P.; Wegerich, Y.; Livrea, P.; Almeida, O.F. Disassembly of shank and homer synaptic clusters is driven by soluble β-amyloid1-40 through divergent NMDAR-dependent signalling pathways. PLoS ONE 2009, 4, e6011. [Google Scholar] [CrossRef] [PubMed]
  133. De Luca, V.; Annesi, G.; De Marco, E.V.; de Bartolomeis, A.; Nicoletti, G.; Pugliese, P.; Muscettola, G.; Barone, P.; Quattrone, A. Homer1 promoter analysis in Parkinson’s disease: Association study with psychotic symptoms. Neuropsychobiology 2009, 59, 239–245. [Google Scholar] [CrossRef] [PubMed]
  134. Chen, T.; Yang, Y.F.; Luo, P.; Liu, W.; Dai, S.H.; Zheng, X.R.; Fei, Z.; Jiang, X.F. Homer1 knockdown protects dopamine neurons through regulating calcium homeostasis in an in vitro model of Parkinson’s disease. Cell Signal. 2013, 25, 2863–2870. [Google Scholar] [CrossRef] [PubMed]
  135. Huang, W.D.; Fei, Z.; Zhang, X. Traumatic injury induced homer-1a gene expression in cultured cortical neurons of rat. Neurosci. Lett. 2005, 389, 46–50. [Google Scholar] [CrossRef] [PubMed]
  136. Wang, Y.; Rao, W.; Zhang, C.; Zhang, C.; Liu, M.D.; Han, F.; Yao, L.B.; Han, H.; Luo, P.; Su, N.; et al. Scaffolding protein Homer1a protects against NMDA-induced neuronal injury. Cell Death Dis. 2015, 6, e1843. [Google Scholar] [CrossRef] [PubMed]
  137. Iasevoli, F.; Ambesi-Impiombato, A.; Fiore, G.; Panariello, F.; Muscettola, G.; de Bartolomeis, A. Pattern of acute induction of Homer1a gene is preserved after chronic treatment with first- and second-generation antipsychotics: Effect of short-term drug discontinuation and comparison with Homer1a-interacting genes. J. Psychopharmacol. 2011, 25, 875–887. [Google Scholar] [CrossRef] [PubMed]
  138. Iasevoli, F.; Ambesi-Impiombato, A.; Fiore, G.; Panariello, F.; Muscettola, G.; de Bartolomeis, A. Topographical and temporal distribution of Homer1a expression is correlated to antipsychotics dopaminergic profile. Eur. Neuropsychopharmacol. 2008, 18, S15–S16. [Google Scholar] [CrossRef]
  139. Gilks, W.P.; Allott, E.H.; Donohoe, G.; Cummings, E.; International Schizophrenia, C.; Gill, M.; Corvin, A.P.; Morris, D.W. Replicated genetic evidence supports a role for HOMER2 in schizophrenia. Neurosci. Lett. 2010, 468, 229–233. [Google Scholar] [CrossRef] [PubMed]
  140. Smothers, C.T.; Szumlinski, K.K.; Worley, P.F.; Woodward, J.J. Altered NMDA receptor function in primary cultures of hippocampal neurons from mice lacking the Homer2 gene. Synapse 2016, 70, 33–39. [Google Scholar] [CrossRef] [PubMed]
  141. Haider, A.; Woodward, N.C.; Lominac, K.D.; Sacramento, A.D.; Klugmann, M.; Bell, R.L.; Szumlinski, K.K. Homer2 within the nucleus accumbens core bidirectionally regulates alcohol intake by both P and Wistar rats. Alcohol 2015, 49, 533–542. [Google Scholar] [CrossRef] [PubMed]
  142. Meyers, J.L.; Salling, M.C.; Almli, L.M.; Ratanatharathorn, A.; Uddin, M.; Galea, S.; Wildman, D.E.; Aiello, A.E.; Bradley, B.; Ressler, K.; et al. Frequency of alcohol consumption in humans; the role of metabotropic glutamate receptors and downstream signaling pathways. Transl. Psychiatry 2015, 5, e586. [Google Scholar] [CrossRef] [PubMed]
  143. Ruegsegger, C.; Stucki, D.M.; Steiner, S.; Angliker, N.; Radecke, J.; Keller, E.; Zuber, B.; Ruegg, M.A.; Saxena, S. Impaired mTORC1-Dependent Expression of Homer-3 Influences SCA1 Pathophysiology. Neuron 2016, 89, 129–146. [Google Scholar] [CrossRef] [PubMed]
  144. Jarius, S.; Wildemann, B. ‘Medusa-head ataxia’: The expanding spectrum of Purkinje cell antibodies in autoimmune cerebellar ataxia. Part 1: Anti-mGluR1, anti-Homer-3, anti-Sj/ITPR1 and anti-CARP VIII. J. Neuroinflamm. 2015, 12, 166. [Google Scholar] [CrossRef] [PubMed]
  145. Matosin, N.; Fernandez-Enright, F.; Lum, J.S.; Engel, M.; Andrews, J.L.; Gassen, N.C.; Wagner, K.V.; Schmidt, M.V.; Newell, K.A. Molecular evidence of synaptic pathology in the CA1 region in schizophrenia. NPJ Schizophr. 2016, 2, 16022. [Google Scholar] [CrossRef] [PubMed]
  146. Fujita-Jimbo, E.; Tanabe, Y.; Yu, Z.; Kojima, K.; Mori, M.; Li, H.; Iwamoto, S.; Yamagata, T.; Momoi, M.Y.; Momoi, T. The association of GPR85 with PSD-95-neuroligin complex and autism spectrum disorder: A molecular analysis. Mol. Autism 2015, 6, 17. [Google Scholar] [CrossRef] [PubMed]
  147. Toro, C.; Deakin, J.F. NMDA receptor subunit NRI and postsynaptic protein PSD-95 in hippocampus and orbitofrontal cortex in schizophrenia and mood disorder. Schizophr. Res. 2005, 80, 323–330. [Google Scholar] [CrossRef] [PubMed]
  148. Kristiansen, L.V.; Meador-Woodruff, J.H. Abnormal striatal expression of transcripts encoding NMDA interacting PSD proteins in schizophrenia, bipolar disorder and major depression. Schizophr. Res. 2005, 78, 87–93. [Google Scholar] [CrossRef] [PubMed]
  149. Seo, M.K.; Lee, C.H.; Cho, H.Y.; You, Y.S.; Lee, B.J.; Lee, J.G.; Park, S.W.; Kim, Y.H. Effects of antipsychotic drugs on the expression of synapse-associated proteins in the frontal cortex of rats subjected to immobilization stress. Psychiatry Res. 2015, 229, 968–974. [Google Scholar] [CrossRef] [PubMed]
  150. De Bartolomeis, A.; Sarappa, C.; Buonaguro, E.F.; Marmo, F.; Eramo, A.; Tomasetti, C.; Iasevoli, F. Different effects of the NMDA receptor antagonists ketamine, MK-801, and memantine on postsynaptic density transcripts and their topography: Role of Homer signaling, and implications for novel antipsychotic and pro-cognitive targets in psychosis. Prog. Neuropsychopharmacol. Biol. Psychiatry 2013, 46, 1–12. [Google Scholar] [CrossRef] [PubMed]
  151. Schmeisser, M.J. Translational neurobiology in Shank mutant mice—Model systems for neuropsychiatric disorders. Ann. Anat. 2015, 200, 115–117. [Google Scholar] [CrossRef] [PubMed]
  152. Zhang, J.; Sun, X.Y.; Zhang, L.Y. MicroRNA-7/Shank3 axis involved in schizophrenia pathogenesis. J. Clin. Neurosci. 2015, 22, 1254–1257. [Google Scholar] [CrossRef] [PubMed]
  153. Sala, C.; Vicidomini, C.; Bigi, I.; Mossa, A.; Verpelli, C. Shank synaptic scaffold proteins: Keys to understanding the pathogenesis of autism and other synaptic disorders. J. Neurochem. 2015, 135, 849–858. [Google Scholar] [CrossRef] [PubMed]
  154. Gong, X.; Wang, H. SHANK1 and autism spectrum disorders. Sci. China Life Sci. 2015, 58, 985–990. [Google Scholar] [CrossRef] [PubMed]
  155. Mashayekhi, F.; Mizban, N.; Bidabadi, E.; Salehi, Z. The Association of SHANK3 Gene Polymorphism and Autism. Minerva Pediatr. 2016. Available online: http://europepmc.org/abstract/med/27271042 (accessed on 20 October 2016). [Google Scholar]
  156. Tamura, M.; Mukai, J.; Gordon, J.A.; Gogos, J.A. Developmental Inhibition of Gsk3 Rescues Behavioral and Neurophysiological Deficits in a Mouse Model of Schizophrenia Predisposition. Neuron 2016, 89, 1100–1109. [Google Scholar] [CrossRef] [PubMed]
  157. Dachtler, J.; Elliott, C.; Rodgers, R.J.; Baillie, G.S.; Clapcote, S.J. Missense mutation in DISC1 C-terminal coiled-coil has GSK3beta signaling and sex-dependent behavioral effects in mice. Sci. Rep. 2016, 6, 18748. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  158. Del’Guidice, T.; Latapy, C.; Rampino, A.; Khlghatyan, J.; Lemasson, M.; Gelao, B.; Quarto, T.; Rizzo, G.; Barbeau, A.; Lamarre, C.; et al. FXR1P is a GSK3beta substrate regulating mood and emotion processing. Proc. Natl. Acad. Sci. USA 2015, 112, E4610–E4619. [Google Scholar] [CrossRef] [PubMed]
  159. Chen, J.; Wang, M.; Waheed Khan, R.A.; He, K.; Wang, Q.; Li, Z.; Shen, J.; Song, Z.; Li, W.; Wen, Z.; et al. The GSK3B gene confers risk for both major depressive disorder and schizophrenia in the Han Chinese population. J. Affect. Disord. 2015, 185, 149–155. [Google Scholar] [CrossRef] [PubMed]
  160. Luca, A.; Calandra, C.; Luca, M. Gsk3 Signalling and Redox Status in Bipolar Disorder: Evidence from Lithium Efficacy. Oxidative Med. Cell. Longev. 2016, 2016, 3030547. [Google Scholar] [CrossRef] [PubMed]
  161. Madison, J.M.; Zhou, F.; Nigam, A.; Hussain, A.; Barker, D.D.; Nehme, R.; van der Ven, K.; Hsu, J.; Wolf, P.; Fleishman, M.; et al. Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol. Psychiatry 2015, 20, 703–717. [Google Scholar] [CrossRef] [PubMed]
  162. Pan, B.; Huang, X.F.; Deng, C. Aripiprazole and Haloperidol Activate GSK3beta-Dependent Signalling Pathway Differentially in Various Brain Regions of Rats. Int. J. Mol. Sci. 2016, 17, 459. [Google Scholar] [CrossRef] [PubMed]
  163. Peng, L.; Zhang, X.; Cui, X.; Zhu, D.; Wu, J.; Sun, D.; Yue, Q.; Li, Z.; Liu, H.; Li, G.; et al. Paliperidone protects SK-N-SH cells against glutamate toxicity via Akt1/GSK3β signaling pathway. Schizophr. Res. 2014, 157, 120–127. [Google Scholar] [CrossRef] [PubMed]
  164. Sutton, L.P.; Rushlow, W.J. The effects of neuropsychiatric drugs on glycogen synthase kinase-3 signaling. Neuroscience 2011, 199, 116–124. [Google Scholar] [CrossRef] [PubMed]
  165. Beaulieu, J.M.; Gainetdinov, R.R.; Caron, M.G. Akt/GSK3 signaling in the action of psychotropic drugs. Annu. Rev. Pharmacol. Toxicol. 2009, 49, 327–347. [Google Scholar] [CrossRef] [PubMed]
  166. Xing, B.; Liang, X.P.; Liu, P.; Zhao, Y.; Chu, Z.; Dang, Y.H. Valproate Inhibits Methamphetamine Induced Hyperactivity via Glycogen Synthase Kinase 3beta Signaling in the Nucleus Accumbens Core. PLoS ONE 2015, 10, e0128068. [Google Scholar] [CrossRef] [PubMed]
  167. Niwa, M.; Cash-Padgett, T.; Kubo, K.I.; Saito, A.; Ishii, K.; Sumitomo, A.; Taniguchi, Y.; Ishizuka, K.; Jaaro-Peled, H.; Tomoda, T.; et al. DISC1 a key molecular lead in psychiatry and neurodevelopment: No-More Disrupted-in-Schizophrenia 1. Mol. Psychiatry 2016, 21, 1488–1489. [Google Scholar] [CrossRef] [PubMed]
  168. Shao, L.; Golbaz, K.; Honer, W.G.; Beasley, C.L. Deficits in axon-associated proteins in prefrontal white matter in bipolar disorder but not schizophrenia. Bipolar Disord. 2016, 18, 342–351. [Google Scholar] [CrossRef] [PubMed]
  169. Munoz-Estrada, J.; Benitez-King, G.; Berlanga, C.; Meza, I. Altered subcellular distribution of the 75-kDa DISC1 isoform, cAMP accumulation, and decreased neuronal migration in schizophrenia and bipolar disorder: Implications for neurodevelopment. CNS Neurosci. Ther. 2015, 21, 446–453. [Google Scholar] [CrossRef] [PubMed]
  170. Chiba, S.; Hashimoto, R.; Hattori, S.; Yohda, M.; Lipska, B.; Weinberger, D.R.; Kunugi, H. Effect of antipsychotic drugs on DISC1 and dysbindin expression in mouse frontal cortex and hippocampus. J. Neural Transm. 2006, 113, 1337–1346. [Google Scholar] [CrossRef] [PubMed]
  171. Mouaffak, F.; Kebir, O.; Chayet, M.; Tordjman, S.; Vacheron, M.N.; Millet, B.; Jaafari, N.; Bellon, A.; Olie, J.P.; Krebs, M.O. Association of Disrupted in Schizophrenia 1 (DISC1) missense variants with ultra-resistant schizophrenia. Pharmacogenom. J. 2011, 11, 267–273. [Google Scholar] [CrossRef] [PubMed]
  172. Robison, A.J. Emerging role of CaMKII in neuropsychiatric disease. Trends Neurosci. 2014, 37, 653–662. [Google Scholar] [CrossRef] [PubMed]
  173. Li, K.; Zhou, T.; Liao, L.; Yang, Z.; Wong, C.; Henn, F.; Malinow, R.; Yates III, J.R.; Hu, H. betaCaMKII in lateral habenula mediates core symptoms of depression. Science 2013, 341, 1016–1020. [Google Scholar] [CrossRef] [PubMed]
  174. Purkayastha, S.; Ford, J.; Kanjilal, B.; Diallo, S.; Del Rosario Inigo, J.; Neuwirth, L.; El Idrissi, A.; Ahmed, Z.; Wieraszko, A.; Azmitia, E.C.; et al. Clozapine functions through the prefrontal cortex serotonin 1A receptor to heighten neuronal activity via calmodulin kinase II-NMDA receptor interactions. J. Neurochem. 2012, 120, 396–407. [Google Scholar] [CrossRef] [PubMed]
  175. Rushlow, W.J.; Seah, C.; Sutton, L.P.; Bjelica, A.; Rajakumar, N. Antipsychotics affect multiple calcium calmodulin dependent proteins. Neuroscience 2009, 161, 877–886. [Google Scholar] [CrossRef] [PubMed]
  176. Browning, J.L.; Patel, T.; Brandt, P.C.; Young, K.A.; Holcomb, L.A.; Hicks, P.B. Clozapine and the mitogen-activated protein kinase signal transduction pathway: Implications for antipsychotic actions. Biol. Psychiatry 2005, 57, 617–623. [Google Scholar] [CrossRef] [PubMed]
  177. Robison, A.J.; Vialou, V.; Sun, H.S.; Labonte, B.; Golden, S.A.; Dias, C.; Turecki, G.; Tamminga, C.; Russo, S.; Mazei-Robison, M.; et al. Fluoxetine epigenetically alters the CaMKIIα promoter in nucleus accumbens to regulate DFosB binding and antidepressant effects. Neuropsychopharmacology 2014, 39, 1178–1186. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Schematic representation of how postsynaptic density (PSD) proteins elaborate and integrate multiple transductional pathways starting at main dopamine and glutamate membrane receptors. Scaffolding proteins (Homer, Shank, PSD-95) physically connect receptors, linking them to intracellular calcium stores. Transductional pathways activated by dopamine receptors closely interconnect with glutamatergic ones via key PSD proteins, such as GSK3, which elaborates and regulates neuronal survival and differentiation. All transductional pathways route receptors signaling to appropriate nuclear targets via specific effectors, such as CaMK, MAPKs, or Erk, in order to finely modulate long-term activity-dependent neuronal rearrangements. The call-outs describe the impact on some crucial PSD molecules by psychopharmacologic drugs, as discussed in the text. NMDAR, N-methyl-d-aspartate glutamate receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor; mGluR1a/5, metabotropic glutamate receptor type 1a/5; TARP, transmembrane AMPA receptors regulating protein or stargazin; PSD-95, postsynaptic density protein 95kD; DISC1, disrupted in schizophrenia 1; GSK3, glycogen synthase kinase 3; PDE4, phosphodiesterase 4; GKAP, guanylate kinase associated protein; H1a, Homer1a immediate-early inducible protein; PIP2, phosphatydilinositol bisphosphate; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; cAMP, cyclic adenosine monophosphate; ER, endoplasmic reticulum; PLC, phospholipase C; PKC, protein kinase C; PKA, protein kinase A; CAMK, calcium-calmodulin regulated kinase; MAPKs, mitogen-activated protein kinases; Erk, extracellular signal-regulated kinase; MEK, MAPK/Erk kinase; and Rac1, Ras-related C3 botulinum toxin substrate 1.
Figure 1. Schematic representation of how postsynaptic density (PSD) proteins elaborate and integrate multiple transductional pathways starting at main dopamine and glutamate membrane receptors. Scaffolding proteins (Homer, Shank, PSD-95) physically connect receptors, linking them to intracellular calcium stores. Transductional pathways activated by dopamine receptors closely interconnect with glutamatergic ones via key PSD proteins, such as GSK3, which elaborates and regulates neuronal survival and differentiation. All transductional pathways route receptors signaling to appropriate nuclear targets via specific effectors, such as CaMK, MAPKs, or Erk, in order to finely modulate long-term activity-dependent neuronal rearrangements. The call-outs describe the impact on some crucial PSD molecules by psychopharmacologic drugs, as discussed in the text. NMDAR, N-methyl-d-aspartate glutamate receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor; mGluR1a/5, metabotropic glutamate receptor type 1a/5; TARP, transmembrane AMPA receptors regulating protein or stargazin; PSD-95, postsynaptic density protein 95kD; DISC1, disrupted in schizophrenia 1; GSK3, glycogen synthase kinase 3; PDE4, phosphodiesterase 4; GKAP, guanylate kinase associated protein; H1a, Homer1a immediate-early inducible protein; PIP2, phosphatydilinositol bisphosphate; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; cAMP, cyclic adenosine monophosphate; ER, endoplasmic reticulum; PLC, phospholipase C; PKC, protein kinase C; PKA, protein kinase A; CAMK, calcium-calmodulin regulated kinase; MAPKs, mitogen-activated protein kinases; Erk, extracellular signal-regulated kinase; MEK, MAPK/Erk kinase; and Rac1, Ras-related C3 botulinum toxin substrate 1.
Ijms 18 00135 g001
Table 1. PSD molecules involvement in major neuropsychiatric disorders and their modulation by main psychopharmacologic treatments.
Table 1. PSD molecules involvement in major neuropsychiatric disorders and their modulation by main psychopharmacologic treatments.
PSD MoleculeInvolvement in Major Neuropsychiatric DisordersModulation by Psychopharmacologic Drugs
Homer 1-Schizophrenia [2,65,66,115,116,117,118]
-Bipolar Disorder [9]
-Major Depressive Disorder [119,120]
-Drug addiction [121,122,123,124,125,126,127,128]
-Chronic inflammatory pain [129,130]
-Fragile X Syndrome [131]
-Alzheimer’s Disease [132]
-Parkinson’s Disease [133,134]
-Traumatic brain injury [135,136]
-Homer 1a may be differentially modulated by both first generation and second generation antipsychotics tightly depending on their own individual receptor profile [42,61,62,137,138]
-The mood stabilizers lithium and valproate have scarce effects on Homer 1a expression, whereas they deeply impact synaptic structure conformation by modulating constitutive Homer 1b/c gene expression [71]
-Combination of antipsychotics and mood stabilizers elicits changes in Homer 1a gene expression that are substantially different from those induced by these drugs individually administered [72]
-Antidepressants and serotonin-modulating antipsychotics induce peculiar cortical expression of Homer 1a in brain regions relevant for negative and cognitive symptoms of schizophrenia [62,84]
Homer 2-Schizophrenia [139]
-Alcohol abuse [140,141,142]
-Chronic haloperidol and clozapine administration may induce overexpression of Homer 2 in lateral septum in animal models [62]
Homer 3-Cerebellar ataxias [143,144]
PSD-95-Schizophrenia [46,145]
-Autism Spectrum Disorders [46,146]
-Bipolar Disorder [9,147]
-Major Depressive Disorder [148]
-Lurasidone and fluoxetine decrease PSD-95 expression in prefrontal cortex and hippocampus [81]
-Olanzapine and aripiprazole may reverse the immobilization stress-induced decrease in PSD-95 levels in frontal cortex [149]
-PSD-95 is crucial for serotonin 5HT2A and 5HT2C receptors expression and abolishing its expression in knockout animals impairs atypical antipsychotics effects [64]
-Ketamine impacts PSD-95 expression in cortical and striatal regions [150], and PSD-95 seems to be crucial for ketamine antidepressant effects [95]
Shank-Schizophrenia [44,151,152]
-Autism Spectrum Disorders [153,154,155]
-The mood stabilizers lithium and valproate may down-regulate Shank cortical expression when chronically administered in animal models [71]
GSK3β-Schizophrenia [156,157,158,159]
-Major Depressive Disorder [158,159]
-Bipolar Disorder [160,161]
-Aripiprazole activates GSK3β signaling in prefrontal cortex and nucleus accumbens, whereas haloperidol activates GSK3β signaling only in nucleus accumbens [162]
-Paliperidone exerts protective effects on neurons via decreasing glutamate-induced overactivation of GSK3β signaling [163]
-Clozapine may increase GSK3β signaling in prefrontal cortex, but not in striatum, where it is activated by haloperidol [164]
-Fluoxetine and imipramine have scarce effects on GSK3β signaling [164]
-The inhibition of GSK3β signaling seems to be a crucial mechanism explaining mood stabilizing effects of lithium [165]
-Valproate inhibits metamphetamine-induced hyperlocomotion via decreasing GSK3β activity [166]
DISC1-Schizophrenia [157,167]
-Bipolar Disorder [168,169]
-Atypical antipsychotics may increase cortical expression of DISC1, whereas typical antipsychotics have no effects [170]
-Specific genomic variants in DISC1 gene in humans have been associated to ultra-resistance to antipsychotic treatment [171]
CAMKII-Schizophrenia [172]
-Major Depressive Disorder [173]
-Clozapine-induced increase in prefrontal cortex activity is crucially mediated by CAMKII-NMDA receptor interactions [174]
-Clozapine, haloperidol and risperidone may decrease CAMKII expression in striatum in animal models [175]
-CAMKII is essential for clozapine-mediated effects on conditioned avoidance responses in animal models [176]
-Fluoxetine may induce changes in CAMKII promoter [177]

Share and Cite

MDPI and ACS Style

Tomasetti, C.; Iasevoli, F.; Buonaguro, E.F.; De Berardis, D.; Fornaro, M.; Fiengo, A.L.C.; Martinotti, G.; Orsolini, L.; Valchera, A.; Di Giannantonio, M.; et al. Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions. Int. J. Mol. Sci. 2017, 18, 135. https://doi.org/10.3390/ijms18010135

AMA Style

Tomasetti C, Iasevoli F, Buonaguro EF, De Berardis D, Fornaro M, Fiengo ALC, Martinotti G, Orsolini L, Valchera A, Di Giannantonio M, et al. Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions. International Journal of Molecular Sciences. 2017; 18(1):135. https://doi.org/10.3390/ijms18010135

Chicago/Turabian Style

Tomasetti, Carmine, Felice Iasevoli, Elisabetta Filomena Buonaguro, Domenico De Berardis, Michele Fornaro, Annastasia Lucia Carmela Fiengo, Giovanni Martinotti, Laura Orsolini, Alessandro Valchera, Massimo Di Giannantonio, and et al. 2017. "Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions" International Journal of Molecular Sciences 18, no. 1: 135. https://doi.org/10.3390/ijms18010135

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop