Chapter 6 - Serotonergic neurons in the treatment of mood disorders: The dialogue with astrocytes
Section snippets
Organization of the serotonergic system and role in the regulation of mood
Serotonin (5-hydroxytryptamine; 5-HT) is one of the main neurotransmitters of the central nervous system (CNS) regulating physiological and behavioral functions. In particular, 5-HT has been shown to modulate body temperature, sleep, food intake, sexual function and emotional states. Serotonergic projections in the CNS arise from the brainstem raphe nuclei. The dorsal raphe nuclei (DR) and the median raphe nuclei (MR) innervate the forebrain and, as such, are considered important in modulating
Overview of the role of astrocytes in mood disorders
It is now well accepted that astrocytes influence synaptic plasticity and neuronal transmission. This property makes them prone to modulate specific neuronal circuits and related behaviors in physiological as well as pathological processes (Volterra and Meldolesi, 2005). As an example, MD has been associated with impairments in the production of new neurons (neurogenesis) or in the establishment of new synapses (Christoffel et al., 2011) and several arguments support the idea that glial cells
A tight control of mood and serotonergic system by the main gliotransmitters
As previously presented, astrocytes are involved in glutamatergic, d-serine and ATP/Adenosine pathways. As those systems are impaired in MD, dissociating the particular function of neurons and astrocytes in terms of gliotransmission functions is of paramount importance but requires newly developed tools (Xie et al., 2015) to specify the role of each cell compartment.
BDNF
The therapeutic activity of SSRIs relies on long-term adaptation and notably on their ability to stimulate adult hippocampal neurogenesis, whereas the disruption of this phenomenon prevents the behavioral effects of these antidepressants in mice (Santarelli et al., 2003). A number of factors have been proposed to participate in SSRI-induced adult hippocampal neurogenesis, and especially brain-derived neurotrophic factor (BDNF). BDNF is the most abundant neurotrophin in the brain and is
Conclusion
One of the most remarkable concepts illustrated in the chapter, is the fact that plasma, CSF and/or brain levels of gliotransmitters are altered in MD and in relevant animal models. The role of gliotransmitters in the regulation of emotional state is further supported by the observation that serotonergic antidepressant drugs are also able to control their extracellular levels in the brain. Interestingly, it seems that the pro-depressive or antidepressant-like effects of gliotransmitter depend
Acknowledgments
The authors' research presented here was supported by MCST grant No. REP-2020-006—CanEpiRisk, University of Malta Research Excellence Fund grant No. I20LU11, MCST grant No. IPAS-2019-019, MCST grant No. R&I 2013-01 EPILEFREE, and ERUK grant No. P1202 Epilepsy Research UK.
References (237)
- et al.
Median raphe serotonin neurons promote anxiety-like behavior via inputs to the dorsal hippocampus
Neuropharmacology
(2020) - et al.
Gliotransmitters travel in time and space
Neuron
(2014) - et al.
S100B and response to treatment in major depression: a pilot study
Eur. Neuropsychopharmacol.
(2003) - et al.
Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study
Biol. Psychiatry
(2000) - et al.
Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells
Neuropsychopharmacology
(1996) - et al.
Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors
Biol. Psychiatry
(2008) - et al.
Behavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: relevance for neuropsychiatric disorders
Behav. Brain Res.
(2009) - et al.
BDNF—a key transducer of antidepressant effects
Neuropharmacology
(2016) - et al.
Raphe serotonin neurons are not homogenous: electrophysiological, morphological and neurochemical evidence
Neuropharmacology
(2011) - et al.
Intravenous administration of adenosine triphosphate and phosphocreatine combined with fluoxetine in major depressive disorder: protocol for a randomized, double-blind, placebo-controlled pilot study
Trials
(2019)
Glial cell abnormalities in major psychiatric disorders: the evidence and implications
Brain Res. Bull.
L-alpha-amino adipic acid provokes depression-like behaviour and a stress related increase in dendritic spine density in the pre-limbic cortex and hippocampus in rodents
Behav. Brain Res.
Disruption of the HPA-axis through corticosterone-release pellets induces robust depressive-like behavior and reduced BDNF levels in mice
Neurosci. Lett.
Fluoxetine and citalopram decrease microglial release of glutamate and D-serine to promote cortical neuronal viability following ischemic insult
Mol. Cell. Neurosci.
Monoamine involvement in the antidepressant-like effect induced by P2 blockade
Brain Res.
Deletion of serine racemase confers D-serine -dependent resilience to chronic social defeat stress
Neurochem. Int.
Developmental regulation of early serotonergic neuronal differentiation: the role of brain-derived neurotrophic factor and membrane depolarization
Dev. Biol.
Effects of ethanol and 5-HT1A agonists on astroglial S100B
Brain Res. Dev. Brain Res.
Dysfunction of astrocyte connexins 30 and 43 in dorsal lateral prefrontal cortex of suicide completers
Biol. Psychiatry
A P2X7 receptor antagonist reverses behavioural alterations, microglial activation and neuroendocrine dysregulation in an unpredictable chronic mild stress (UCMS) model of depression in mice
Psychoneuroendocrinology
Rapid anxiolytic effects of RS67333, a serotonin type 4 receptor agonist, and diazepam, a benzodiazepine, are mediated by projections from the prefrontal cortex to the dorsal raphe nucleus
Biol. Psychiatry
In vivo knockdown of astroglial glutamate transporters GLT-1 and GLAST increases excitatory neurotransmission in mouse infralimbic cortex: relevance for depressive-like phenotypes
Eur. Neuropsychopharmacol.
Astrocyte control of glutamatergic activity: downstream effects on serotonergic function and emotional behavior
Neuropharmacology
Pharmacological and genetic approaches to study connexin-mediated channels in glial cells of the central nervous system
Brain Res. Rev.
Region specific decrease in glial fibrillary acidic protein immunoreactivity in the brain of a rat model of depression
Neuroscience
5-Hydroxytryptamine stimulates the formation of inositol phosphate in astrocytes from different regions of the brain
Neuropharmacology
Increased levels of glutamate in brains from patients with mood disorders
Biol. Psychiatry
Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior
Neuron
Dysfunction of astrocytic connexins 30 and 43 in the medial prefrontal cortex and hippocampus mediates depressive-like behaviours
Behav. Brain Res.
Cerebrospinal fluid D-serine concentrations in major depressive disorder negatively correlate with depression severity
J. Affect. Disord.
Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors: possibly involvement of metallothionein expression in astrocytes
Neurochem. Int.
The plastic d-serine signaling pathway: sliding from neurons to glia and vice-versa
Neurosci. Lett.
Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor
Biol. Psychiatry
Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors
Neurosci. Lett.
Pharmacological evidence for the involvement of the opioid system in the antidepressant-like effect of adenosine in the mouse forced swimming test
Eur. J. Pharmacol.
Involvement of NMDA receptors in the antidepressant-like action of adenosine
Pharmacol. Rep.
Antidepressant amitriptyline-induced matrix metalloproteinase-9 activation is mediated by Src family tyrosine kinase, which leads to glial cell line-derived neurotrophic factor mRNA expression in rat astroglial cells
Neuropsychopharmacol. Rep.
TrkB signaling in dorsal raphe nucleus is essential for antidepressant efficacy and normal aggression behavior
Neuropsychopharmacology
The GDNF family: signalling, biological functions and therapeutic value
Nat. Rev. Neurosci.
Both aging and chronic fluoxetine increase S100B content in the mouse hippocampus
Neuroreport
Fluoxetine regulates the expression of neurotrophic/growth factors and glucose metabolism in astrocytes
Psychopharmacology (Berl)
Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder
Bipolar Disord.
Clozapine and olanzapine, but not haloperidol, suppress serotonin efflux in the medial prefrontal cortex elicited by phencyclidine and ketamine
Int. J. Neuropsychopharmacol.
Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus
Nature
Serotonin neuron diversity in the dorsal raphe
ACS Chem. Nerosci.
5-HT1A receptor-mediated autoinhibition and the control of serotonergic cell firing
ACS Chem. Nerosci.
Antidepressant-like effects induced by chronic blockade of the purinergic 2X7 receptor through inhibition of non-like receptor protein 1 inflammasome in chronic unpredictable mild stress model of depression in rats
Clin. Psychopharmacol. Neurosci.
Treatment with the neurotrophic protein S100B increases synaptogenesis after traumatic brain injury
J. Neurotrauma
Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole
Mol. Psychiatry
Purinergic signaling and related biomarkers in depression
Brain Sci.
Cited by (3)
Multiple facets of serotonergic modulation
2021, Progress in Brain ResearchCitation Excerpt :These 5-HT receptor subtypes regulate distinct physiological processes, through different and sometimes opposing signaling pathways (Hoyer and Martin, 1997; Hoyer and Schoeffter, 1991). The 5-HT system has been shown to interact with an impressive amount of neurochemical systems and some of them have been listed in Table 1. These interactions concern several chemical classes ranging from fast amino acid neurotransmitters (e.g., glutamate and GABA), neuromodulators (e.g., dopamine, noradrenaline), neuropeptides (e.g., corticotropin-releasing factor, Neuropeptide Y), regulatory transmitters (e.g., endocannabinoids) and even glial and endothelial factors (e.g., astrocytes, see Table 1).
Cytokine signalling at the microglial penta-partite synapse
2021, International Journal of Molecular Sciences