NMDAR dysfunction and the regulation of dopaminergic transmission in schizophrenia

A substantial body of evidence implicates dysfunction in N -methyl- D -aspartate receptors (NMDARs) in the pathophysiology of schizophrenia. This article illustrates how NMDAR dysfunction may give rise to many of the neurobiological phenomena frequently associated with schizophrenia with a particular focus on how NMDAR dysfunction affects the thalamic reticular nucleus (nRT) and pedunculopontine tegmental nucleus (PPTg). Furthermore, this article presents a model for schizophrenia illustrating how dysfunction in the nRT may interrupt prefrontal regulation of midbrain dopaminergic neurons, and how dysfunction in the PPTg may drive increased, irregular burst firing.


Introduction
Though the biological bases of schizophrenia are not fully understood, a number of elements common to many patients have been identified.Historically, two of the most prominent and influential theories are the dopamine hypothesis, which implicates excessive dopaminergic transmission from the midbrain to the striatum and reduced transmission to cortical regions (Howes and Kapur, 2009;Meltzer and Stahl, 1976;Seeman, 1987;Stahl, 2018); and the glutamate hypothesis, which implicates dysfunction in N-methyl-D-aspartate type glutamate receptors (NMDARs) (Javitt, 1987;Javitt et al., 2012;Stahl, 2018;Uno and Coyle, 2019).In addition to dopamine and glutamate, dysfunction in γ-aminobutyric acid (GABA) synthesis and transmission (Guidotti et al., 2000;Perry et al., 1979), cortical thinning (Dietsche et al., 2017;Zhao et al., 2022), oligodendrocyte dysfunction and decreased myelin integrity (Davis et al., 2003;Takahashi et al., 2011), redox dysregulation and inflammation (Steullet et al., 2016), and alterations in delta and gamma band oscillations (Galderisi et al., 2009;Uhlhaas and Singer, 2010) have all been observed in patients or implicated in the pathophysiology of the disorder.In spite of their disparity, there is evidence to suggest that many of these observations follow as a consequence of NMDAR dysfunction.
This article presents a model for schizophrenia that considers how NMDAR dysfunction may underlie many of the phenomena frequently observed in patients with a particular focus on its effects on the thalamic reticular nucleus (nRT) and pedunculopontine tegmental nucleus (PPTg).Drawing on evidence from the dopamine and glutamate hypotheses and GABAergic dysfunction, this model illustrates how NMDAR dysfunction may be particularly consequential for GABAergic interneurons in the hippocampus, nRT and PPTg; that nRT dysfunction may interrupt prefrontal regulation of midbrain dopaminergic transmission; dysfunction in the PPTg may increase dopaminergic output, and dopaminergic transmission to the nRT may create positive feedback that elicits hallucinatory episodes.
It is important to note that the complex and heterogenous nature of schizophrenia under current clinical definitions precludes an allencompassing theory regarding its underlying pathophysiology, and the overlap it shares with other psychotic disorders in terms of susceptibility genes, phenotypes, and pharmaceutical treatments can make it difficult to disentangle what pertains to schizophrenia specifically and psychosis generally (Clementz et al., 2015;Ethridge et al., 2015;Gershon et al., 2011;Wong et al., 2010).Thus, the model presented in this article may be considered one of many potential mechanisms underlying psychosis with the caveat that it is largely informed by data collected from patients with a diagnosis of schizophrenia.

Dopamine
Implication of dopamine in the pathophysiology of schizophrenia began with the introduction of the neuroleptics chlorpromazine and reserpine into psychiatry in the early 1950's by Jean Delay and his assistant Pierre Deniker (Delay et al., 1952;Müller et al., 1952).A report by Delay on treatment of psychotic patients with chlorpromazine revealed that it was able to alleviate hallucinations and stop voices in eight of the treated patients (Delay, 1952;Seeman, 2006).Although Carlsson and Lindqvist (1963) suggested that chlorpromazine and haloperidol, another neuroleptic, may work by blocking monoaminergic receptors, the first study specifically implicating dopamine is generally credited to Van Rossum (1967).Van Rossum's postulate drew on evidence showing that dopamine receptors were involved in the central action of dexamphetamine and cocaine, that this amphetamine action could be antagonised by neuroleptics, and that neuroleptics could, in turn, block dopamine receptors.At the time, frequent use of cocaine and amphetamines was also associated with the development of psychotic symptoms resembling those of schizophrenia (Connell, 1957) and later found to be related to dopaminergic activity (Ellison, 1994;Kokkinidis and Anisman, 1981;Snyder, 1972).
Subsequent studies through the 1970's, particularly those of neuropharmacologist Philip Seeman, found that the effectiveness of neuroleptics, or antipsychotics as they are alternately known (López-Muñoz et al., 2005), was strongly correlated with their ability to block D2 type dopamine receptors (Creese et al., 1976;Seeman and Lee, 1975;Seeman et al., 1976) but that no such correlation was observed with D1, D3, or D4 receptors (Seeman, 1980(Seeman, , 1987(Seeman, , 2006)).Neuroimaging studies have consistently found increased dopamine in the striatum of schizophrenia patients (McCutcheon et al., 2019) (striatal hyperdopaminergia) and decreased dopamine in cortical regions (cortical hypodopaminergia) (Frankle et al., 2022), further supporting a role for dysfunctional dopaminergic transmission in the pathophysiology of the disorder.Dopaminergic neurons exhibit two activity states related to their firing pattern known as tonic and phasic states (Grace, 1991).At rest, dopaminergic cells in the VTA are tonically active, spontaneously firing at low frequencies (1-5 Hz).Exposure to behaviourally salient stimuli follows with a high frequency phasic burst (≥20 Hz) (Grace and Gomes, 2019;Wenzel et al., 2015).Similar burst firing patterns occur along nigrostriatal, mesolimbic, and mesocortical pathways in response to a wide variety of salient stimuli and arousing events including appetitive, aversive, intense, and novel stimuli (Horvitz, 2000) and are largely driven by glutamatergic projections originating in the PPTg (Galtieri et al., 2017).However, in order to respond to a switch to phasic activity, dopaminergic neurons must first be depolarised and spontaneously active.The proportion of dopaminergic neurons that are spontaneously active and thereby responsive to phasic activation, i.e. the population activity, may be adjusted by inhibitory GABAergic projections from the ventral pallidum.In this manner, the ventral pallidum may be thought of as a form of gain control, with the PPTg inciting a switch to phasic activity, and the ventral pallidum regulating the number of dopaminergic neurons that respond (Floresco et al., 2003;Grace, 2010;Grace and Gomes, 2019;Sonnenschein et al., 2020).Evidence shows that the increase in striatal dopamine observed in patients is related to increases in irregular phasic bursts (i.e., phasic bursts not apparently related to exposure to salient stimuli), rather than elevated tonic activity, and that cocaine and amphetamines produce similar increases in irregular phasic activity (Covey et al., 2014;Daberkow et al., 2013;Maia and Frank, 2017).
Though early theories regarding dopaminergic dysfunction in schizophrenia implicated hyperdopaminergia along the mesolimbic pathway, i.e. dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens in the ventral striatum, later studies have indicated dysfunction to be greater in the nigrostriatal pathway, i. e. dopaminergic projections from the substantia nigra (SN) to the striatum (Molochnikov and Cohen, 2014); more specifically that increases in synaptic dopamine and dopamine synthesis capacity were more pronounced in the associative striatum (Howes et al., 2011;Kegeles et al., 2010;Kesby et al., 2018;Laruelle and Abi-Dargham, 1999;Winton-Brown et al., 2014).
A substantial body of evidence identifies striatal hyperdopaminergia as a core component of schizophrenia, as elevated striatal dopamine synthesis has been identified in both medicated and medication naïve patients, individuals in the prodromal phase, and patients' first-degree relatives (Bloomfield and Howes, 2020).However, similar elevations in striatal dopamine synthesis capacity have also been found in other mental disorders with psychotic symptoms such as bipolar affective disorder, and shown to correlate with symptom severity (Jauhar et al., 2017).This suggests that striatal hyperdopaminergia may not be unique to schizophrenia, but rather a transdiagnostic feature of positive psychotic symptoms such as hallucinations and delusions (Bloomfield and Howes, 2020).On the other hand, the prevalence of treatment-resistant schizophrenia (TRS), in which symptoms persist despite antipsychotic treatment (Howes et al., 2016), and the identification of striatal hyperdopaminergia among patients' first-degree relatives that do not display symptoms suggests other mechanisms may be involved.Finally, there is little evidence in support of a primary pathology in dopaminergic transmission as an aetiological factor in schizophrenia (Grace, 2000).Taken together, this suggests that while striatal hyperdopaminergia and prefrontal hypodopaminergia may be a core component of psychotic symptoms, alone they may not necessarily be sufficient to produce them and other mechanisms may be involved.The glutamate hypothesis, a complementary rather than competitive hypothesis, implicates dysfunctional glutamate receptors in the pathophysiology of schizophrenia.

Glutamate
Development of the glutamate hypothesis was initially based on pharmacological studies that found NMDAR antagonists such as phencyclidine (PCP) and ketamine could reproduce symptoms of schizophrenia in healthy individuals and exacerbate symptoms in patients.Prolonged, chronic use of these substances may also elicit a psychosis that is difficult to distinguish from schizophrenia (Javitt et al., 2012;Nakazawa and Sapkota, 2020;Stahl, 2018).Additionally, a number of genes involved in NMDAR expression and related to their function have been implicated in schizophrenia (Chumakov et al., 2002;Detera-Wadleigh and McMahon, 2006;Lisman et al., 2008;Petryshen et al., 2005;Stefansson et al., 2002;Stefansson et al., 2003).Furthermore, anti-NMDAR encephalitis, an autoimmune disease in which antibodies cause internalisation of NMDARs from the cell membrane, produces a syndrome resembling first-episode psychosis and is often misdiagnosed as idiopathic schizophrenia (Al-Diwani et al., 2019;Nakazawa and Sapkota, 2020;Venkatesan and Adatia, 2017).Studies have also found that administration of PCP, ketamine, and MK-801, a similar noncompetitive NMDAR antagonist, may lead to increased striatal dopamine release in rodents, but evidence as to whether this also occurs in humans or non-human primates is currently inconclusive (Kokkinou et al., 2018;Nakazawa and Sapkota, 2020).
Glutamate receptors fall broadly into two categories: metabotropic receptors and ionotropic receptors.NMDARs, along with α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and kainate receptors comprise the three classes of ionotropic receptor (Brady et al., 2011).All three receptors are nonselective cation channels in that their activation allows passage of sodium and potassium ions into the cell.However, NMDARs are distinguished by three unique features.Firstly, activation of the AMPA and kainate receptors requires only binding of glutamate to the receptor, whereas NMDAR activation requires simultaneous binding of both glutamate and either L-glycine or Dserine.Secondly, at resting potential the NMDAR channel pore is blocked by a magnesium ion (Mg 2+ ) which is removed by depolarisation of the neuron, normally through activation of AMPA and kainate receptors on the same neuron.Thirdly, in addition to potassium and sodium, NMDARs also allow passage of calcium ions (Ca 2+ ) into the cell (Lau and Tymianski, 2010;Lüscher and Malenka, 2012;Nakazawa and Sapkota, 2020).Steullet et al. (2016) identifies a three-way reciprocal relationship between NMDAR hypofunction, neuroinflammation and redox dysregulation that forms a "central hub" in schizophrenia pathophysiology, where an imbalance any one of these systems subsequently affects the other two.They further emphasise that dysfunction in these hub systems has particularly deleterious effects on the normal development of both oligodendrocytes, which may account for observed decreases in myelin integrity in patients; and parvalbumin-positive (PV+) GABAergic interneurons.This also helps to illustrate why the aetiology of schizophrenia remains so elusive, as many genetic, environmental, and developmental factors implicated in schizophrenia that may appear disparate may be related through this hub, and factors that do not appear to affect NMDAR function directly may work indirectly through their effect on redox dysregulation and neuroinflammation.
Unlike dopamine, NMDARs are ubiquitous throughout the brain, which raises questions as to why certain processes appear to be more dependent on NMDAR mediated transmission, and why certain cellular subtypes may be more susceptible to their dysfunction.Furthermore, excitatory post-synaptic potentials (EPSPs) in pyramidal cells are primarily generated by AMPA receptors, with NMDARs being mainly involved in synaptic plasticity and potentiation.In this light it seems unclear how NMDAR dysfunction should affect processes not directly related to plasticity or potentiation (Lisman et al., 2008).However, studies have found that EPSPs that activate GABAergic fast-spiking interneurons (FSIs) are largely mediated by NMDARs, more so than AMPA and kainate receptors (Jones and Bühl, 1993;Maccaferri and Dingledine, 2002).Following from models of psychosis based on dissociative anaesthetics and anti-NMDAR encephalitis, Nakazawa and Sapkota (2020) suggest that since both the non-competitive NMDAR antagonists such as ketamine, PCP and MK-801, and anti-NMDAR-antibodies preferentially bind to receptors in their open state, i.e. when the Mg 2+ block has been removed, and that open channel probability is directly related to firing rate, GABAergic fast-spiking interneurons (FSIs) may be particularly susceptible to NMDAR dysfunction.

GABA
Though the term "GABA hypothesis" does not exist in the literature with the same prominence as the dopamine and glutamate hypotheses, there is substantial evidence for dysfunction in synthesis and transmission of GABA in schizophrenia patients.Early evidence stems from post-mortem studies that found reduced glutamic acid decarboxylase (GAD) activity in the nucleus accumbens, amygdala and hippocampus (Bird et al., 1977) as well as reduced GABA content in the nucleus accumbens and thalamus (Perry et al., 1979) of schizophrenia patients compared to healthy controls.Subsequent studies have consistently found reduced GAD mRNA expression, particularly in the dorsolateral prefrontal cortex (DLPFC), and it has since become one of the most widely replicated findings in schizophrenia research (Gonzalez-Burgos et al., 2010;Lodge et al., 2009;Nakazawa et al., 2012).Reductions in the number or density of non-pyramidal, putative GABAergic interneurons, have also been observed in the hippocampus of both patients with schizophrenia and bipolar disorder; whereas the number of pyramidal cells between patients and controls was found to be similar (Benes et al., 1998;Heckers and Konradi, 2015).Studies have also found that in prefrontal cortical regions there is a decrease in the calcium binding protein parvalbumin, but no significant difference in the number of PV+ neurons (Reynolds et al., 2001).It is worth noting that GAD expression is related to neural activity, and that Ca 2+ influx through NMDARs directly influences GAD expression (Lee et al., 2019).
Though many different types of GABAergic interneurons express NMDA receptors, there is evidence to suggest that PV+ FSIs are disproportionately affected by NMDAR dysfunction.In addition to the non-competitive NMDAR antagonist and anti-NMDAR encephalitis models of schizophrenia that implicate PV+ FSIs by virtue of their fastspiking properties, studies using mouse models of NMDAR dysfunction have found that schizophrenia-like abnormalities in dopaminergic transmission arise as a result of selective NMDAR dysfunction in PV+ FSIs but not in somatostatin positive (SST+) type GABAergic interneurons (Nakao et al., 2019;Nakazawa and Sapkota, 2020), and that selective NMDAR ablation in PV+ FSIs results in schizophrenia-like phenotypes, but ablation in neurogliaform type cells does not (Chittajallu et al., 2017).PV+ FSIs play a critical role in the generation of gamma-band oscillations, which are involved in higher brain functions such as cognition, attention and working memory; and have been found to be deficient in schizophrenia patients.(Behrendt and Young, 2004;Cardin et al., 2009;Dienel and Lewis, 2019;Gonzalez-Burgos and Lewis, 2012;Nakazawa et al., 2012;Sohal et al., 2009;Uhlhaas and Singer, 2010).
A number of studies have investigated the effects of loss of PV+ interneurons using an animal model of schizophrenia in which normal development is disrupted by prenatal administration of the DNA methylating agent methylazoxymethanol acetate (MAM).Administration of MAM at embryonic day 17 in pregnant rat dams has been shown to produce changes that parallel observations in schizophrenia patients, including cortical thinning, deficits in prepulse inhibition (PPI) of the startle response, increased dopamine release in response to amphetamine and PCP, and absences of characteristic slow (1 Hz) and fast (40 Hz) field potential oscillations in the medial prefrontal cortex (mPFC) (Goto and Grace, 2006;Lodge and Grace, 2007;Moore et al., 2006).More importantly, prenatal MAM treatment as an animal model for schizophrenia may produce rats with reduced PV+ interneurons in the mPFC and the ventral, but not dorsal, subiculum of the hippocampus (vSub), and evidence suggests that this may drive dysregulation of dopaminergic neurons in the VTA (Lodge et al., 2009;Lodge and Grace, 2007).
In addition to gamma oscillations, disturbances in other electrophysiological phenomena such as reduced sleep spindles during sleep and increased delta oscillations in the awake state have also been observed in schizophrenia patients (Ferrarelli et al., 2007;Ferrarelli et al., 2010;Lisman, 2012;Manoach and Stickgold, 2019;Wamsley et al., 2012;Zhang et al., 2012b), many of which are regulated by thalamocortical circuits under the influence of the thalamic reticular nucleus (nRT).

The thalamic reticular nucleus
The nRT is a thin layer of GABAergic neurons that extends across the dorsolateral aspects of the thalamus.Unlike other thalamic nuclei, the nRT does not project to the cortex, but rather forms GABAergic projections to both first-and higher-order thalamic nuclei.GABAergic neurons of the nRT are innervated by collateral fibres from glutamatergic projections passing both from the cortex to the thalamus and from the thalamus to the cortex as well as cholinergic, serotonergic, and noradrenergic inputs from brainstem nuclei, and dopaminergic inputs from the substantia nigra (Barrientos et al., 2019).In this manner, the nRT is in an anatomically strategic position to modulate the flow of information between the thalamus and cortex (i.e., thalamocortical interactions) (Pratt and Morris, 2015).
Thalamic neurons display a unique property that allows them to engage in two electrophysiological firing modes: tonic firing mode, in which cells are partially depolarised and respond to afferent inputs with single action potentials, and burst firing mode, in which the cell is hyperpolarised and produces a burst of several high frequency action potentials (Behrendt and Young, 2004;Sherman and Guillery, 2013).Burst firing mode is facilitated by T-type (T for transient) calcium channels on the dendrites and soma of thalamic neurons which open at low membrane potentials.When open, these calcium channels lead to an inward calcium current or low-threshold spike (LTS), the presence or absence of which determines which of the two firing modes may be engaged.If a thalamic neuron is initially depolarised by <5 mV for <100 ms, T-type calcium channels remain in the inactivated state and the cell engages in tonic firing mode whereby a suprathreshold depolarisation evokes a string of unitary action potentials.If, however, the neuron is hyperpolarised by >5 mV for longer than 100 ms, T-type calcium channels are de-inactivated and the cell responds to a suprathreshold depolarisation with an LTS and a burst of high frequency action potentials.As with conventional action potentials mediated by sodium channels, there is a refractory period following activation of calcium channels, the kinetics of which are much slower (ca. 100 ms for calcium channels vs. 1 ms for sodium channels).As a result, burstspiking cannot occur at frequency faster than 10 Hz (Sherman and Guillery, 2013).
Considering the influence the nRT exerts over thalamocortical interactions, a compelling body of evidence suggests its dysfunction may constitute a core abnormality in schizophrenia (Pratt et al., 2017).Firstly, the nRT is involved in attentional modulation, generation of sleep spindles, establishing cortical gamma and delta band oscillations, and emotional salience (see Pratt and Morris (2015) for a comprehensive review), as well as the mismatch negativity (MMN) potential (Lakatos et al., 2020), all of which have been demonstrated to be disrupted or affected in patients with schizophrenia.Secondly, a number of genes related to schizophrenia, including DISC1 (Disrupted-in-Schizophrenia 1) and ErbB4 are highly expressed in the nRT (Ahrens et al., 2015;Pratt and Morris, 2015;Richard et al., 2017;Steullet, 2020).It is worth noting that these two genes, as well as neuregulin-1, an endogenous ligand for the ErbB4 receptor, have all been related to proper glutamatergic function, with the DISC1 protein specifically related to NMDAR hypofunction.Additionally, signalling between neuregulin-1 and ErbB4 has been implicated in depolarisation-induced GABAergic transmission (Woo et al., 2007).Thirdly, studies investigating the effects of PCP on markers for glutamatergic and GABAergic function and metabolism in the rat brain found that chronic, intermittent administration of PCP could lead to decreased glucose metabolism in the prefrontal cortex, mimicking human hypofrontality as observed in schizophrenia patients.Similar observations were also made in the nRT and the substantia nigra, but the changes in the nRT preceded those in both the prefrontal cortex and substantia nigra, with nRT changes observed 2 h post-treatment and changes in the prefrontal cortex and substantia nigra not observed until after 24 h post-treatment (Cochran et al., 2002;Cochran et al., 2003).Finally, NMDARs in the nRT express high levels of the NR2C type subunit, which creates NMDARs that are only weakly blocked by Mg 2+ (Karavanova et al., 2007;Zhang et al., 2012a;Zhang et al., 2009).Under the arguments put forward by Nakazawa and Sapkota (2020) this also makes them particularly susceptible to the effects of non-competitive NMDAR antagonists and anti-NMDAR encephalitis.The effect of this weak magnesium block in the nRT is that these receptors may be partially activated by ambient glutamate.Normally, this would help maintain the membrane potential in these cells above the threshold for de-inactivating T-type calcium channels, hindering burst firing.However, when these NMDARs are either dysfunctional or blocked, the cell may be more easily hyperpolarised.Zhang et al. (2009) demonstrated that this may trigger bursting at delta band frequency, and that dopamine appears to play a role in generating these delta bursts as they may be abolished with the application of a D2 receptor antagonist (eticlopride).Increased delta power, even in waking states, is another phenomenon frequently observed in schizophrenia patients, even in unmedicated patients (Boutros et al., 2008;Kim et al., 2015;Sponheim et al., 1994).
In addition to the roles the nRT plays implicating it in the pathophysiology of schizophrenia there is evidence to suggest that its dysfunction may also disrupt prefrontal regulation of dopaminergic neurons, creating the hypodopaminergic state characteristic of schizophrenia and related psychoses.

Prefrontal regulation of midbrain dopaminergic neurons
The activity of dopaminergic neurons in the VTA is influenced by prefrontal cortical regions including the prelimbic prefrontal cortex (plPFC) and the infralimbic prefrontal cortex (ilPFC) through a polysynaptic pathway outlined in Fig. 1 (Sonnenschein et al., 2020;Zhu et al., 2021;Zimmerman and Grace, 2016).
The nucleus reuniens (RE) receives excitatory inputs directly from the ilPFC and collateral inhibitory inputs from the nRT.The RE densely innervates the cornu ammonis 1 (CA1) region and vSub of the hippocampus (Lisman et al., 2010;Sonnenschein et al., 2020;Zimmerman and Grace, 2016), however it should be noted that these projections appear to be modulatory, as direct electrical stimulation of afferents from the RE elicits sub-threshold depolarisation of pyramidal cells, effectively enhancing their excitability (Dolleman- Van der Weel et al., 1997).The CA1 and vSub form excitatory projections to the nucleus accumbens in the ventral striatum, which in turn inhibits the ventral pallidum.Inhibition of the ventral pallidum hinders inhibition of dopaminergic cells, increasing population activity and hence, the dopaminergic response to a switch to phasic activity.
Though Lodge and Grace (2007) found that prenatal administration of MAM in rats could lead to increased hippocampal activity and subsequently increase spontaneous firing in VTA dopaminergic neurons, a more recent study by Zhu et al. (2021) using a similar MAM animal model demonstrated that inducing oxidative impairments to the anterior nRT could create a deficit of inhibition to the RE, shifting pathway dominance to excitatory projections directly from the ilPFC and increasing activity in the RE.Studies have also shown that administration of systemic NMDAR antagonists in rats increases activity in the nRT and midline thalamic nuclei including the RE (Lisman et al., 2010;Väisänen et al., 2004).Taken together, there is evidence to show that NMDAR dysfunction in the nRT may lead to increased activity in the RE.Subsequent effects on the hippocampus, nucleus accumbens, and ventral pallidum connect further to disinhibition of midbrain dopaminergic neurons.Lisman et al. (2010) suggest that the increased dopaminergic response in midbrain neurons may lead to increased dopamine levels in the thalamus, which in turn hyperpolarises nRT cells.This hyperpolarisation works in concert with the hyperpolarisation already caused by dysfunctional NMDARs to reach the threshold for deinactivation of Ttype calcium channels and promotes burst firing.This increase in burst firing has the potential to create positive feedback by further disrupting communication between prefrontal regions and the RE, and subsequently the CA1 and vSub regions of the hippocampus (Fig. 1).
A recent study by Hugdahl et al. (2023) investigating the temporal signatures of auditory-verbal hallucinations, one of the hallmark symptoms of schizophrenia, using functional magnetic resonance imaging (fMRI) identified a region in the ventromedial prefrontal cortex (vmPFC), a region that contains the ilPFC in humans, that showed increased activity in the seconds before the onset of hallucinatory episodes and decreased activity seconds before their cessation.Given this, the authors suggest that this activity seen in the vmPFC of individuals experiencing hallucinations may correspond to the ilPFC and, in the presence of a dysfunctional nRT, lead to excess excitation of the nucleus reuniens through the pathway outlined in Fig. 1.
Dysfunction in the nRT has been implicated in the biological mechanisms underlying hallucinations as a transdiagnostic phenomenon across a range of neurological and psychiatric conditions, not only in schizophrenia patients (Behrendt, 2003(Behrendt, , 2006;;Behrendt and Young, 2004;Esmaeeli et al., 2019;Ferrarelli and Tononi, 2011).The authors suggest that the increase in activity observed in the vmPFC in the seconds preceding a hallucinatory episode marks the first step in the series of events outlined in Fig. 1.NMDAR dysfunction in nRT cells is sufficient to disrupt communication between prefrontal regions and the nucleus reuniens, but the release of dopamine in the thalamus this leads to further compromises the nRT past a threshold where hallucinations emerge.
Thus, NMDAR dysfunction in the nRT may create dopaminergic feedback that gives rise to hallucinations through the interruption of communication between prefrontal regions and thalamic nuclei.However, as stated previously, schizophrenia is marked by increases in irregular phasic bursts rather than elevated tonic activity, and that increases are greater along nigrostriatal pathways than mesostriatal.Thus, it is important to consider the PPTg and its role in regulating phasic activity in dopaminergic neurons, particularly in the substantia nigra (Galtieri et al., 2017).

The pedunculopontine tegmental nucleus
The PPTg has been implicated in the pathophysiology of schizophrenia due to its role in regulating states of consciousness, more specifically arousal and rapid eye movement (REM) sleep, as part of the reticular activating system (RAS) (Garcia-Rill et al., 2015).Schizophrenia is associated with shorter REM sleep latency and increased REM sleep drive (Chan et al., 2017;Ferrarelli, 2021), which is suggestive of an overactive RAS and elevated activity in the PPTg (Garcia-Rill et al., 2015;Smith and Terhune, 2023).Additionally, the PPTg is involved in PPI, which has consistently been found to be reduced in schizophrenia patients (Mena et al., 2016).Garcia-Rill et al. (2019) illustrates how neurons in the PPTg may be categorised into groups of "threes" based on the neurotransmitter they release, the type of calcium channels they express, and their in vivo firing pattern.Thus, the PPTg contains cholinergic, glutamatergic and GABAergic neurons; they may express N-type, P/Q-type or both N-and P/Q-type calcium channels; and display three types of in vivo firing pattern related to sleep and wakefulness: "REM on" cells that are active during REM sleep, "wake on" cells active during waking, and "wake-REM on" cells that are active during both REM sleep and waking.Studies have shown that cholinergic PPTg neurons that project to the thalamus are primarily active during wakefulness and REM sleep and that their firing decreases during non-REM sleep (Benarroch, 2013;Mahesh et al., 1998).These cholinergic inputs appear to control transitions to wakefulness from sleep by activating thalamocortical neurons and inhibiting nRT neurons, facilitating a transition from synchronous, burst-firing states characteristic of non-REM sleep to tonic activity characteristic of wakefulness and REM sleep (McCormick and Bal, 1997).It appears that the "waking" pathway arising from the PPTg is mediated by P/Qtype calcium channels whose activation is modulated by NMDARs, and the REM sleep pathway is mediated by N-type calcium channels whose activation is modulated by kainate receptors (Garcia-Rill et al., 2019) A study by Datta et al. (2001b) showed that microinjection of glutamate into the PPTg of free moving rats could increase both the amount of time in REM sleep and wakefulness.A subsequent study (Datta et al., 2001a) found that pretreatment with an NMDAR specific antagonist could block glutamate induced wakefulness and preserve normal amounts of sleep and wakefulness.This suggests an important role specifically for NMDARs in mediating a "waking" pathway from the PPTg that promotes wakefulness (Garcia-Rill et al., 2019).This is particularly interesting, as there are theories suggesting that hallucinations may represent the intrusion of REM sleep on waking states (Garcia-Rill et al., 2015).Gottesmann (2006) illustrates how REM sleep and schizophrenia share a similar neurobiological support, as both are characterised by deactivation in prefrontal cortical regions, disturbed responsiveness and sensory deafferentation, and identical variations in acetylcholine, noradrenaline, dopamine, serotonin, and glutamate levels.Most notably, during REM sleep, dopaminergic transmission to the striatum increases and transmission to prefrontal regions decreases, which parallels the striatal hyperdopaminergia and prefrontal hypodopaminergia characteristic of schizophrenia.Similarities between dreaming and psychosis in schizophrenia are further supported by observations that dopaminergic agonists, such as those used in the treatment of Parkinson's disease, and glutamate receptor antagonists induce not only psychosis but also vivid dreaming, and that nightmares related to posttraumatic stress disorder have been successfully treated using neuroleptics (Jakovljević et al., 2003).Furthermore there is evidence, albeit limited, that irregular burst firing in dopaminergic neurons occurs during REM sleep more so than during slow wave sleep (Gottesmann, 2004(Gottesmann, , 2006)).It is possible, and fitting with the proposed model, that dysfunction in NMDARs may compromise the waking pathway arising from the PPTg, and this may manifest in increased, irregular burst firing in midbrain dopaminergic neurons, including nigrostriatal projections.

Discussion
This article provides a simplified framework illustrating how NMDAR dysfunction may give rise to many of the neurobiological and related phenomena frequently associated with schizophrenia.To summarise: Steullet et al. (2016) illustrates a three-way reciprocal relationship between neuroinflammation, redox dysregulation and NMDAR hypofunction, and how numerous genetic and environmental may contribute to any of these core elements and, through reciprocal interactions, elicit the other two.The disruption of these elements appears to have disruptive effects particularly on oligodendrocytes, which may account for the decreased myelin integrity observed in schizophrenia, and PV+ FSIs, which are involved in the generation of gamma band oscillations, also found to be deficient in schizophrenia patients.Though PV+ FSIs are ubiquitous throughout the brain, in the nRT they are particularly dependent on the proper function of NMDARs for the regulation of burst-and tonic-firing modes.Dysfunction in NMDARs in the nRT may interrupt communication between prefrontal regions and thalamic nuclei, such that there is an excess of excitation from prefrontal regions, leading to excess activity in thalamic nuclei which leads, through a polysynaptic pathway, to disinhibition of midbrain dopaminergic neurons.There is also evidence to suggest the existence of a "waking" pathway arising from the PPTg that is dependent on NMDARs.NMDAR dysfunction may compromise the activation of this pathway and lead to irregular burst firing of disinhibited midbrain dopaminergic neurons characteristic of schizophrenia.Dopaminergic feedback to the nRT may create delta oscillations in the nRT and further compromise proper function past a threshold where hallucinations emerge.
This article has largely focused on neurobiological phenomena associated with schizophrenia.Though beyond the scope of this article, there is evidence linking nRT dysfunction to hallucinations (Behrendt, 2003(Behrendt, , 2006;;Behrendt and Young, 2004;Esmaeeli et al., 2019;Ferrarelli and Tononi, 2011), striatal hyperdopaminergia to delusions (Howes et al., 2020;Kapur, 2003;Kapur et al., 2005), and NMDAR dysfunction in the PPTg to dissociation (Smith and Terhune, 2023).The authors intend to illustrate how NMDAR dysfunction and the model outlined in this article may give rise to many of the characteristic symptoms of schizophrenia in a future article.
As stated previously, the diverse and heterogenous nature of schizophrenia, under current clinical definitions, as well as overlap and comorbidities it shares with other mental disorders, precludes an allencompassing model.However, as Fig. 1 illustrates, there are numerous nodes in the model where dysfunction may occur and drive a similar effect.For example, dysfunction in the nRT may compromise prefrontal regulation of dopaminergic neurons, but dysfunction in the hippocampus or ventral pallidum directly may also lead to disinhibition of midbrain dopaminergic neurons.Furthermore, this model does not imply that dysfunction in NMDARs or PV+ FSIs does not have consequences elsewhere in the brain, rather it focuses on the nRT and PPTg as key components in the pathophysiology of schizophrenia.
The findings of Hugdahl et al. (2023) regarding prefrontal activity surrounding the occurrence of hallucinatory episodes are interesting, and raise an important question: If increased activity in the vmPFC may elicit an hallucinatory episode, what is it that drives the corresponding decrease in activity observed in the seconds preceding the cessation of hallucinations?It is, however, first necessary to find further evidence in support of the suggested model, and whether activity in prefrontal regions does elicit a dopaminergic response in hallucinating individuals.Future studies may benefit from combining this design with, for example, dynamic positron emission tomography (PET) (i.e., combined PET/fMRI) in order to investigate whether dopamine levels increase accordingly in response to activity in the vmPFC, or by combining fMRI with electroencephalography (EEG) to determine whether they are marked by increased delta bursting.
Finally, the model proposed in this article highlights an important role for the PPTg, and it would be interesting to investigate whether an NMDAR dependent waking pathway from this region drives irregular burst firing in midbrain dopaminergic neurons.

Declaration of competing interest
None.