Publications by authors named "Naguib Mechawar"

111 Publications

Parvalbumin interneuron alterations in stress-related mood disorders: A systematic review.

Neurobiol Stress 2021 Nov 12;15:100380. Epub 2021 Aug 12.

Stress-related psychiatric disorders including depression involve complex cellular and molecular changes in the brain, and GABAergic signaling dysfunction is increasingly implicated in the etiology of mood disorders. Parvalbumin (PV)-expressing neurons are fast-spiking interneurons that, among other roles, coordinate synchronous neuronal firing. Mounting evidence suggests that the PV neuron phenotype is altered by stress and in mood disorders. In this systematic review, we assessed PV interneuron alterations in psychiatric disorders as reported in human postmortem brain studies and animal models of environmental stress. This review aims to 1) comprehensively catalog evidence of PV cell function in mood disorders (humans) and stress models of mood disorders (animals); 2) analyze the strength of evidence of PV interneuron alterations in various brain regions in humans and rodents; 3) determine whether the modulating effect of antidepressant treatment, physical exercise, and environmental enrichment on stress in animals associates with particular effects on PV function; and 4) use this information to guide future research avenues. Its principal findings, derived mainly from rodent studies, are that stress-related changes in PV cells are only reported in a minority of studies, that positive findings are region-, age-, sex-, and stress recency-dependent, and that antidepressants protect from stress-induced apparent PV cell loss. These observations do not currently translate well to humans, although the postmortem literature on the topic remains limited.
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http://dx.doi.org/10.1016/j.ynstr.2021.100380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446799PMC
November 2021

The emerging tale of microglia in psychiatric disorders.

Neurosci Biobehav Rev 2021 Sep 15;131:1-29. Epub 2021 Sep 15.

McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University, Montreal, QC, Canada. Electronic address:

As the professional phagocytes of the brain, microglia orchestrate the immunological response and play an increasingly important role in maintaining homeostatic brain functions. Microglia are activated by pathological events or slight alterations in brain homeostasis. This activation is dependent on the context and type of stressor or pathology. Through secretion of cytokines, chemokines and growth factors, microglia can strongly influence the response to a stressor and can, therefore, determine the pathological outcome. Psychopathologies have repeatedly been associated with long-lasting priming and sensitization of cerebral microglia. This review focuses on the diversity of microglial phenotype and function in health and psychiatric disease. We first discuss the diverse homeostatic functions performed by microglia and then elaborate on context-specific spatial and temporal microglial heterogeneity. Subsequently, we summarize microglia involvement in psychopathologies, namely major depressive disorder, schizophrenia and bipolar disorder, with a particular focus on post-mortem studies. Finally, we postulate microglia as a promising novel therapeutic target in psychiatry through antidepressant and antipsychotic treatment.
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http://dx.doi.org/10.1016/j.neubiorev.2021.09.023DOI Listing
September 2021

Effects of Early Life Stress on the Developing Basolateral Amygdala-Prefrontal Cortex Circuit: The Emerging Role of Local Inhibition and Perineuronal Nets.

Front Hum Neurosci 2021 26;15:669120. Epub 2021 Aug 26.

Douglas Mental Health University Institute, Montreal, QC, Canada.

The links between early life stress (ELS) and the emergence of psychopathology such as increased anxiety and depression are now well established, although the specific neurobiological and developmental mechanisms that translate ELS into poor health outcomes are still unclear. The consequences of ELS are complex because they depend on the form and severity of early stress, duration, and age of exposure as well as co-occurrence with other forms of physical or psychological trauma. The long term effects of ELS on the corticolimbic circuit underlying emotional and social behavior are particularly salient because ELS occurs during critical developmental periods in the establishment of this circuit, its local balance of inhibition:excitation and its connections with other neuronal pathways. Using examples drawn from the human and rodent literature, we review some of the consequences of ELS on the development of the corticolimbic circuit and how it might impact fear regulation in a sex- and hemispheric-dependent manner in both humans and rodents. We explore the effects of ELS on local inhibitory neurons and the formation of perineuronal nets (PNNs) that terminate critical periods of plasticity and promote the formation of stable local networks. Overall, the bulk of ELS studies report transient and/or long lasting alterations in both glutamatergic circuits and local inhibitory interneurons (INs) and their associated PNNs. Since the activity of INs plays a key role in the maturation of cortical regions and the formation of local field potentials, alterations in these INs triggered by ELS might critically participate in the development of psychiatric disorders in adulthood, including impaired fear extinction and anxiety behavior.
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http://dx.doi.org/10.3389/fnhum.2021.669120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426628PMC
August 2021

Neuron-derived extracellular vesicles enriched from plasma show altered size and miRNA cargo as a function of antidepressant drug response.

Mol Psychiatry 2021 Aug 12. Epub 2021 Aug 12.

McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.

Previous work has demonstrated that microRNAs (miRNAs) change as a function of antidepressant treatment (ADT) response. However, it is unclear how representative these peripherally detected miRNA changes are to those occurring in the brain. This study aimed to use peripherally extracted neuron-derived extracellular vesicles (NDEV) to circumvent these limitations and investigate neuronal miRNA changes associated with antidepressant response. Samples were collected at two time points (baseline and after 8 weeks of follow-up) from depressed patients who responded (N = 20) and did not respond (N = 20) to escitalopram treatment, as well as controls (N = 20). Total extracellular vesicles (EVs) were extracted from plasma, and then further enriched for NDEV by immunoprecipitation with L1CAM. EVs and NDEVs were characterized, and NDEV miRNA cargo was extracted and sequenced. Subsequently, studies in cell lines and postmortem tissue were conducted. Characterization of NDEVs revealed that they were smaller than other EVs isolated from plasma (p < 0.0001), had brain-specific neuronal markers, and contained miRNAs enriched for brain functions (p < 0.0001) Furthermore, NDEVs from depressed patients were smaller than controls (p < 0.05), and NDEV size increased with ADT response (p < 0.01). Finally, changes in NDEV cargo, specifically changes in miR-21-5p, miR-30d-5p, and miR-486-5p together (p < 0.01), were associated with ADT response. Targets of these three miRNAs were altered in brain tissue from depressed individuals (p < 0.05). Together, this study indicates that changes in peripherally isolated NDEV can act as both a clinically accessible and informative biomarker of ADT response specifically through size and cargo.
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http://dx.doi.org/10.1038/s41380-021-01255-2DOI Listing
August 2021

Lesch-Nyhan disease causes impaired energy metabolism and reduced developmental potential in midbrain dopaminergic cells.

Stem Cell Reports 2021 Jul 1;16(7):1749-1762. Epub 2021 Jul 1.

Psychiatric Genetics Group, McGill University, Montreal, QC, Canada; Department of Psychiatry, McGill University and Douglas Hospital Research Institute, 6875 LaSalle Boulevard, Frank Common Building, Room 2101.2, Montreal, QC H4H 1R3, Canada. Electronic address:

Mutations in HPRT1, a gene encoding a rate-limiting enzyme for purine salvage, cause Lesch-Nyhan disease which is characterized by self-injury and motor impairments. We leveraged stem cell and genetic engineering technologies to model the disease in isogenic and patient-derived forebrain and midbrain cell types. Dopaminergic progenitor cells deficient in HPRT showed decreased intensity of all developmental cell-fate markers measured. Metabolic analyses revealed significant loss of all purine derivatives, except hypoxanthine, and impaired glycolysis and oxidative phosphorylation. real-time glucose tracing demonstrated increased shunting to the pentose phosphate pathway for de novo purine synthesis at the expense of ATP production. Purine depletion in dopaminergic progenitor cells resulted in loss of RHEB, impairing mTORC1 activation. These data demonstrate dopaminergic-specific effects of purine salvage deficiency and unexpectedly reveal that dopaminergic progenitor cells are programmed to a high-energy state prior to higher energy demands of terminally differentiated cells.
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http://dx.doi.org/10.1016/j.stemcr.2021.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282463PMC
July 2021

Extraction of nuclei from archived postmortem tissues for single-nucleus sequencing applications.

Nat Protoc 2021 06 10;16(6):2788-2801. Epub 2021 May 10.

McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, Canada.

Single-cell and single-nucleus sequencing techniques are a burgeoning field with various biological, biomedical and clinical applications. Numerous high- and low-throughput methods have been developed for sequencing the RNA and DNA content of single cells. However, for all these methods, the key requirement is high-quality input of a single-cell or single-nucleus suspension. Preparing such a suspension is the limiting step when working with fragile, archived tissues of variable quality. This hurdle can prevent such tissues from being extensively investigated with single-cell technologies. We describe a protocol for preparing single-nucleus suspensions within the span of a few hours that reliably works for multiple postmortem and archived tissue types using standard laboratory equipment. The stages of the protocol include tissue preparation and dissociation, nuclei extraction, and nuclei concentration assessment and capture. The protocol is comparable to other published protocols but does not require fluorescence-assisted nuclei sorting (FANS) or ultracentrifugation. The protocol can be carried out by a competent graduate student familiar with basic laboratory techniques and equipment. Moreover, these preparations are compatible with single-nucleus (sn)RNA-seq and assay for transposase-accessible chromatin (ATAC)-seq using the 10X Genomics Chromium system. The protocol reliably results in efficient capture of single nuclei for high-quality snRNA-seq libraries.
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http://dx.doi.org/10.1038/s41596-021-00514-4DOI Listing
June 2021

Implication of cerebral astrocytes in major depression: A review of fine neuroanatomical evidence in humans.

Glia 2021 Sep 18;69(9):2077-2099. Epub 2021 Mar 18.

McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, Quebec, Canada.

Postmortem investigations have implicated astrocytes in many neurological and psychiatric conditions. Multiple brain regions from individuals with major depressive disorder (MDD) have lower expression levels of astrocyte markers and lower densities of astrocytes labeled for these markers, suggesting a loss of astrocytes in this mental illness. This paper reviews the general properties of human astrocytes, the methods to study them, and the postmortem evidence for astrocyte pathology in MDD. When comparing astrocyte density and morphometry studies, astrocytes are more abundant and smaller in human subcortical than cortical brain regions, and immunohistochemical labeling for the astrocyte markers glial fibrillary acidic protein (GFAP) and vimentin (VIM) reveals fewer than 15% of all astrocytes that are present in cortical and subcortical regions, as revealed using other staining techniques. By combining astrocyte densities and morphometry, a model was made to illustrate that domain organization is mostly limited to GFAP-IR astrocytes. Using these markers and others, alterations of astrocyte densities appear more widespread than those for astrocyte morphologies throughout the brain of individuals having died with MDD. This review suggests how reduced astrocyte densities may relate to the association of depressive episodes in MDD with elevated S100 beta (S100B) cerebrospinal fluid serum levels. Finally, a potassium imbalance theory is proposed that integrates the reduced astrocyte densities generated from postmortem studies with a hypothesis for the antidepressant effects of ketamine generated from rodent studies.
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http://dx.doi.org/10.1002/glia.23994DOI Listing
September 2021

Implication of cerebral astrocytes in major depression: A review of fine neuroanatomical evidence in humans.

Glia 2021 Sep 18;69(9):2077-2099. Epub 2021 Mar 18.

McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, Quebec, Canada.

Postmortem investigations have implicated astrocytes in many neurological and psychiatric conditions. Multiple brain regions from individuals with major depressive disorder (MDD) have lower expression levels of astrocyte markers and lower densities of astrocytes labeled for these markers, suggesting a loss of astrocytes in this mental illness. This paper reviews the general properties of human astrocytes, the methods to study them, and the postmortem evidence for astrocyte pathology in MDD. When comparing astrocyte density and morphometry studies, astrocytes are more abundant and smaller in human subcortical than cortical brain regions, and immunohistochemical labeling for the astrocyte markers glial fibrillary acidic protein (GFAP) and vimentin (VIM) reveals fewer than 15% of all astrocytes that are present in cortical and subcortical regions, as revealed using other staining techniques. By combining astrocyte densities and morphometry, a model was made to illustrate that domain organization is mostly limited to GFAP-IR astrocytes. Using these markers and others, alterations of astrocyte densities appear more widespread than those for astrocyte morphologies throughout the brain of individuals having died with MDD. This review suggests how reduced astrocyte densities may relate to the association of depressive episodes in MDD with elevated S100 beta (S100B) cerebrospinal fluid serum levels. Finally, a potassium imbalance theory is proposed that integrates the reduced astrocyte densities generated from postmortem studies with a hypothesis for the antidepressant effects of ketamine generated from rodent studies.
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http://dx.doi.org/10.1002/glia.23994DOI Listing
September 2021

Non-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation.

Nat Commun 2021 02 18;12(1):1132. Epub 2021 Feb 18.

McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montréal, Canada.

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context. Additionally, we find that ELA associates with methylomic changes that are as frequent in the CAC as in the canonical CG context, while these two forms of plasticity occur in sharply distinct genomic regions, features, and chromatin states. Combining these multiple data indicates that immune-related and small GTPase signaling pathways are most consistently impaired in the amygdala of ELA individuals. Overall, this work provides insights into genomic brain regulation as a function of early-life experience.
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http://dx.doi.org/10.1038/s41467-021-21365-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892573PMC
February 2021

How stress physically re-shapes the brain: Impact on brain cell shapes, numbers and connections in psychiatric disorders.

Neurosci Biobehav Rev 2021 05 5;124:193-215. Epub 2021 Feb 5.

Illawarra Health and Medical Research Institute, Northfields Ave, Wollongong 2522, Australia; Molecular Horizons, School of Chemistry and Molecular Biosciences, University of Wollongong, Northfields Ave, Wollongong 2522, Australia; Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804 Munich, Germany. Electronic address:

Severe stress is among the most robust risk factors for the development of psychiatric disorders. Imaging studies indicate that life stress is integral to shaping the human brain, especially regions involved in processing the stress response. Although this is likely underpinned by changes to the cytoarchitecture of cellular networks in the brain, we are yet to clearly understand how these define a role for stress in human psychopathology. In this review, we consolidate evidence of macro-structural morphometric changes and the cellular mechanisms that likely underlie them. Focusing on stress-sensitive regions of the brain, we illustrate how stress throughout life may lead to persistent remodelling of the both neurons and glia in cellular networks and how these may lead to psychopathology. We support that greater translation of cellular alterations to human cohorts will support parsing the psychological sequalae of severe stress and improve our understanding of how stress shapes the human brain. This will remain a critical step for improving treatment interventions and prevention outcomes.
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http://dx.doi.org/10.1016/j.neubiorev.2021.01.025DOI Listing
May 2021

Severe childhood and adulthood stress associates with neocortical layer-specific reductions of mature spines in psychiatric disorders.

Neurobiol Stress 2020 Nov 21;13:100270. Epub 2020 Nov 21.

Illawarra Health and Medical Research Institute, Northfields Ave, Wollongong, 2522, Australia.

Severe stress exposure causes the loss of dendritic spines on cortical pyramidal neurons and induces psychiatric-like symptoms in rodent models. These effects are strongest following early-life stress and are most persistent on apical dendrites. However, the long-term impacts and temporal effects of stress exposure on the human brain remain poorly understood. Using a novel postmortem cohort of psychiatric cases with severe stress experienced in childhood, adulthood, or no severe stress, and matched controls, we aimed to determine the impact of stress timing on pyramidal neuron structure in the human orbitofrontal cortex (OFC). We performed Golgi Cox staining and manually measured the morphology and density of over 22,000 dendritic spines on layer-specific pyramidal neuron apical dendrites. We also quantified glucocorticoid receptor mRNA and protein as a marker of stress dysregulation. Both childhood and adulthood stress were associated with large reductions in mature mushroom spine density (up to 56% loss) in both the superficial (II/III) and deeper layers (V) of the OFC. However, childhood stress caused more substantial reductions to both total and mature mushroom spines. No difference in glucocorticoid receptor mRNA and protein were seen between groups, although both negatively correlated with total spine density within the whole cohort. These findings indicate that severe stress, especially when experienced during childhood, persistently affects the fine morphological properties of neurons in the human OFC. This may impact on cell connectivity in this brain area, and at least partly explain the social and emotional symptoms that originate in the OFC in psychiatric disorders.
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http://dx.doi.org/10.1016/j.ynstr.2020.100270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739192PMC
November 2020

miR-323a regulates ERBB4 and is involved in depression.

Mol Psychiatry 2020 Nov 20. Epub 2020 Nov 20.

Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QC, Canada.

Major depressive disorder (MDD) is a complex and debilitating illness whose etiology remains unclear. Small RNA molecules, such as micro RNAs (miRNAs) have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified miRNA expression by small RNA sequencing in the anterior cingulate cortex and habenula of individuals with MDD and psychiatrically-healthy controls. Thirty-two miRNAs showed significantly correlated expression between the two regions (False Discovery Rate < 0.05), of which four, miR-204-5p, miR-320b, miR-323a-3p, and miR-331-3p, displayed upregulated expression in MDD. We assessed the expression of predicted target genes of differentially expressed miRNAs in the brain, and found that the expression of erb-b2 receptor tyrosine kinase 4 (ERBB4), a gene encoding a neuregulin receptor, was downregulated in both regions, and was influenced by miR-323a-3p in vitro. Finally, we assessed the effects of manipulating miRNA expression in the mouse ACC on anxiety- and depressive-like behaviors. Mice in which miR-323-3p was overexpressed or knocked-down displayed increased and decreased emotionality, respectively. Additionally, these mice displayed significantly downregulated and upregulated expression of Erbb4, respectively. Overall, our findings indicate the importance of brain miRNAs in the pathology of MDD, and emphasize the involvement of miR-323a-3p and ERBB4 in this phenotype. Future studies further characterizing miR-323a-3p and neuregulin signaling in depression are warranted.
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http://dx.doi.org/10.1038/s41380-020-00953-7DOI Listing
November 2020

Cocaine-related DNA methylation in caudate neurons alters 3D chromatin structure of the IRXA gene cluster.

Mol Psychiatry 2021 Jul 12;26(7):3134-3151. Epub 2020 Oct 12.

McGill Group for Suicide Studies, Douglas Hospital Research Center, Montreal, QC, Canada.

Epigenetic mechanisms, like those involving DNA methylation, are thought to mediate the relationship between chronic cocaine dependence and molecular changes in addiction-related neurocircuitry, but have been understudied in human brain. We initially used reduced representation bisulfite sequencing (RRBS) to generate a methylome-wide profile of cocaine dependence in human post-mortem caudate tissue. We focused on the Iroquois Homeobox A (IRXA) gene cluster, where hypomethylation in exon 3 of IRX2 in neuronal nuclei was associated with cocaine dependence. We replicated this finding in an independent cohort and found similar results in the dorsal striatum from cocaine self-administering mice. Using epigenome editing and 3C assays, we demonstrated a causal relationship between methylation within the IRX2 gene body, CTCF protein binding, three-dimensional (3D) chromatin interaction, and gene expression. Together, these findings suggest that cocaine-related hypomethylation of IRX2 contributes to the development and maintenance of cocaine dependence through alterations in 3D chromatin structure in the caudate nucleus.
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http://dx.doi.org/10.1038/s41380-020-00909-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039060PMC
July 2021

Characterization of Vimentin-Immunoreactive Astrocytes in the Human Brain.

Front Neuroanat 2020 30;14:31. Epub 2020 Jul 30.

McGill Group for Suicide Studies, Douglas Mental Health University Institute, Verdun, QC, Canada.

Astrocytes are commonly identified by their expression of the intermediate filament protein glial fibrillary acidic protein (GFAP). GFAP-immunoreactive (GFAP-IR) astrocytes exhibit regional heterogeneity in density and morphology in the mouse brain as well as morphological diversity in the human cortex. However, regional variations in astrocyte distribution and morphology remain to be assessed comprehensively. This was the overarching objective of this postmortem study, which mainly exploited the immunolabeling of vimentin (VIM), an intermediate filament protein expressed by astrocytes and endothelial cells which presents the advantage of more extensively labeling cell structures. We compared the densities of vimentin-immunoreactive (VIM-IR) and GFAP-IR astrocytes in various brain regions (prefrontal and primary visual cortex, caudate nucleus, mediodorsal thalamus) from male individuals having died suddenly in the absence of neurological or psychiatric conditions. The morphometric properties of VIM-IR in these brain regions were also assessed. We found that VIM-IR astrocytes generally express the canonical astrocytic markers Aldh1L1 and GFAP but that VIM-IR astrocytes are less abundant than GFAP-IR astrocytes in all human brain regions, particularly in the thalamus, where VIM-IR cells were nearly absent. About 20% of all VIM-IR astrocytes presented a twin cell morphology, a phenomenon rarely observed for GFAP-IR astrocytes. Furthermore VIM-IR astrocytes in the striatum were often seen to extend numerous parallel processes which seemed to give rise to large VIM-IR fiber bundles projecting over long distances. Moreover, morphometric analyses revealed that VIM-IR astrocytes were more complex than their mouse counterparts in functionally homologous brain regions, as has been previously reported for GFAP-IR astrocytes. Lastly, the density of GFAP-IR astrocytes in gray and white matter were inversely correlated with vascular density, but for VIM-IR astrocytes this was only the case in gray matter, suggesting that gliovascular interactions may especially influence the regional heterogeneity of GFAP-IR astrocytes. Taken together, these findings reveal special features displayed uniquely by human VIM-IR astrocytes and illustrate that astrocytes display important region- and marker-specific differences in the healthy human brain.
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http://dx.doi.org/10.3389/fnana.2020.00031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406576PMC
July 2020

Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons.

Nat Neurosci 2020 06 27;23(6):771-781. Epub 2020 Apr 27.

McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, Quebec, Canada.

Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment.
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http://dx.doi.org/10.1038/s41593-020-0621-yDOI Listing
June 2020

Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons.

Nat Neurosci 2020 06 27;23(6):771-781. Epub 2020 Apr 27.

McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, Quebec, Canada.

Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment.
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http://dx.doi.org/10.1038/s41593-020-0621-yDOI Listing
June 2020

Characterization of Cerebellum-Specific Ribosomal DNA Epigenetic Modifications in Alzheimer's Disease: Should the Cerebellum Serve as a Control Tissue After All?

Mol Neurobiol 2020 Jun 30;57(6):2563-2571. Epub 2020 Mar 30.

Departamento de Morfologia e Genética, Programa de Pós-Graduação em Biologia Estrutural e Funcional da UNIFESP/EPM, Disciplina de Genética, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, SP, Brazil.

Alzheimer's disease (AD) is a neurodegenerative disease, known as the most common form of dementia. In AD onset, abnormal rRNA expression has been reported to be linked in pathogenesis. Although region-specific expression patterns have previously been reported in AD, it is not until recently that the cerebellum has come under the spotlight. Specifically, it is unclear whether DNA methylation is the mechanism involved in rRNA expression regulation in AD. Hence, we sought to explore the rDNA methylation pattern of two different brain regions - auditory cortex and cerebellum - from AD and age-/sex-matched controls. Our results showed differential hypermethylation at an upstream CpG region to the rDNA promoter when comparing cerebellum controls to auditory cortex controls. This suggests a possible regulatory region from rDNA expression regulation. Moreover, when comparing between AD and control cerebellum samples, we observed hypermethylation of the rDNA promoter region as well as an increase in rDNA content. In addition, we also observed increased rRNA levels in AD compared to control cerebellum. Although still considered a pathology-free brain region, there are growing findings that continue to suggest otherwise. Indeed, cerebellum from AD has been recently described as affected by the disease, presenting a unique pattern of molecular alterations. Given that we observed that increased rDNA promoter methylation did not silence rDNA gene expression, we suggest that rDNA promoter hypermethylation is playing a protective role in rDNA genomic stability and, therefore, increasing rRNA levels in AD cerebellum.
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http://dx.doi.org/10.1007/s12035-020-01902-9DOI Listing
June 2020

Stimulation of L-type calcium channels increases tyrosine hydroxylase and dopamine in ventral midbrain cells induced from somatic cells.

Stem Cells Transl Med 2020 Jun 10;9(6):697-712. Epub 2020 Mar 10.

Psychiatric Genetics Group, McGill University, Montreal, Quebec, Canada.

Making high-quality dopamine (DA)-producing cells for basic biological or small molecule screening studies is critical for the development of novel therapeutics for disorders of the ventral midbrain. Currently, many ventral midbrain assays have low signal-to-noise ratio due to low levels of cellular DA and the rate-limiting enzyme of DA synthesis, tyrosine hydroxylase (TH), hampering discovery efforts. Using intensively characterized ventral midbrain cells derived from human skin, which demonstrate calcium pacemaking activity and classical electrophysiological properties, we show that an L-type calcium agonist can significantly increase TH protein levels and DA content and release. Live calcium imaging suggests that it is the immediate influx of calcium occurring simultaneously in all cells that drives this effect. Genome-wide expression profiling suggests that L-type calcium channel stimulation has a significant effect on specific genes related to DA synthesis and affects expression of L-type calcium receptor subunits from the CACNA1 and CACNA2D families. Together, our findings provide an advance in the ability to increase DA and TH levels to improve the accuracy of disease modeling and small molecule screening for disorders of the ventral midbrain, including Parkinson's disease.
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http://dx.doi.org/10.1002/sctm.18-0180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214648PMC
June 2020

Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression.

Proc Natl Acad Sci U S A 2020 02 23;117(6):3326-3336. Epub 2020 Jan 23.

Department of Psychiatry and Neuroscience, Université Laval, Quebec City, QC G1V 0A6, Canada;

Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood-brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of expression and low endothelium expression of repressive cldn5-related transcription factor are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued expression in the NAc and promoted resilience. Importantly, we confirmed changes in expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious -related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.
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http://dx.doi.org/10.1073/pnas.1914655117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022213PMC
February 2020

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing.

Glia 2020 06 20;68(6):1291-1303. Epub 2020 Jan 20.

Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.

Characterizing the developmental trajectory of oligodendrocyte progenitor cells (OPC) is of great interest given the importance of these cells in the remyelination process. However, studies of human OPC development remain limited by the availability of whole cell samples and material that encompasses a wide age range, including time of peak myelination. In this study, we apply single cell RNA sequencing to viable whole cells across the age span and link transcriptomic signatures of oligodendrocyte-lineage cells with stage-specific functional properties. Cells were isolated from surgical tissue samples of second-trimester fetal, 2-year-old pediatric, 13-year-old adolescent, and adult donors by mechanical and enzymatic digestion, followed by percoll gradient centrifugation. Gene expression was analyzed using droplet-based RNA sequencing (10X Chromium). Louvain clustering analysis identified three distinct cellular subpopulations based on 5,613 genes, comprised of an early OPC (e-OPC) group, a late OPC group (l-OPC), and a mature OL (MOL) group. Gene ontology terms enriched for e-OPCs included cell cycle and development, for l-OPCs included extracellular matrix and cell adhesion, and for MOLs included myelination and cytoskeleton. The e-OPCs were mostly confined to the premyelinating fetal group, and the l-OPCs were most highly represented in the pediatric age group, corresponding to the peak age of myelination. Cells expressing a signature characteristic of l-OPCs were identified in the adult brain in situ using RNAScope. These findings highlight the transcriptomic variability in OL-lineage cells before, during, and after peak myelination and contribute to identifying novel pathways required to achieve remyelination.
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http://dx.doi.org/10.1002/glia.23777DOI Listing
June 2020

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing.

Glia 2020 06 20;68(6):1291-1303. Epub 2020 Jan 20.

Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.

Characterizing the developmental trajectory of oligodendrocyte progenitor cells (OPC) is of great interest given the importance of these cells in the remyelination process. However, studies of human OPC development remain limited by the availability of whole cell samples and material that encompasses a wide age range, including time of peak myelination. In this study, we apply single cell RNA sequencing to viable whole cells across the age span and link transcriptomic signatures of oligodendrocyte-lineage cells with stage-specific functional properties. Cells were isolated from surgical tissue samples of second-trimester fetal, 2-year-old pediatric, 13-year-old adolescent, and adult donors by mechanical and enzymatic digestion, followed by percoll gradient centrifugation. Gene expression was analyzed using droplet-based RNA sequencing (10X Chromium). Louvain clustering analysis identified three distinct cellular subpopulations based on 5,613 genes, comprised of an early OPC (e-OPC) group, a late OPC group (l-OPC), and a mature OL (MOL) group. Gene ontology terms enriched for e-OPCs included cell cycle and development, for l-OPCs included extracellular matrix and cell adhesion, and for MOLs included myelination and cytoskeleton. The e-OPCs were mostly confined to the premyelinating fetal group, and the l-OPCs were most highly represented in the pediatric age group, corresponding to the peak age of myelination. Cells expressing a signature characteristic of l-OPCs were identified in the adult brain in situ using RNAScope. These findings highlight the transcriptomic variability in OL-lineage cells before, during, and after peak myelination and contribute to identifying novel pathways required to achieve remyelination.
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http://dx.doi.org/10.1002/glia.23777DOI Listing
June 2020

The Consortium for the early identification of Alzheimer's disease-Quebec (CIMA-Q).

Alzheimers Dement (Amst) 2019 Dec 20;11:787-796. Epub 2019 Nov 20.

Department of Psychiatry, McGill University, Montreal, Canada.

Introduction: The Consortium for the early identification of Alzheimer's disease-Quebec (CIMA-Q) created a research infrastructure to recruit, characterize, and track disease progression in individuals at risk of dementia.

Methods: CIMA-Q established standardized clinical, neuropsychological, neuroimaging, blood (plasma, serum, RNA, genomic DNA), cryopreserved peripheral blood mononuclear cells, and cerebrospinal fluid collection protocols. These data and biological materials are available to the research community.

Results: In phase 1, 115 persons with subjective cognitive decline, 88 with mild cognitive impairment, 31 with early probable Alzheimer's disease, and 56 older adults with no worries nor impairments received detailed clinical and cognitive evaluations as well as blood and peripheral blood mononuclear cells collections. Among them, 142 underwent magnetic resonance imaging, 29 a fluorodeoxyglucose positron emission tomography, and 60 a lumbar puncture.

Discussion: CIMA-Q provides procedures and resources to identify early biomarkers and novel therapeutic targets, and holds promise for detecting cognitive decline in Alzheimer's disease.
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http://dx.doi.org/10.1016/j.dadm.2019.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880140PMC
December 2019

The Consortium for the early identification of Alzheimer's disease-Quebec (CIMA-Q).

Alzheimers Dement (Amst) 2019 Dec 20;11:787-796. Epub 2019 Nov 20.

Department of Psychiatry, McGill University, Montreal, Canada.

Introduction: The Consortium for the early identification of Alzheimer's disease-Quebec (CIMA-Q) created a research infrastructure to recruit, characterize, and track disease progression in individuals at risk of dementia.

Methods: CIMA-Q established standardized clinical, neuropsychological, neuroimaging, blood (plasma, serum, RNA, genomic DNA), cryopreserved peripheral blood mononuclear cells, and cerebrospinal fluid collection protocols. These data and biological materials are available to the research community.

Results: In phase 1, 115 persons with subjective cognitive decline, 88 with mild cognitive impairment, 31 with early probable Alzheimer's disease, and 56 older adults with no worries nor impairments received detailed clinical and cognitive evaluations as well as blood and peripheral blood mononuclear cells collections. Among them, 142 underwent magnetic resonance imaging, 29 a fluorodeoxyglucose positron emission tomography, and 60 a lumbar puncture.

Discussion: CIMA-Q provides procedures and resources to identify early biomarkers and novel therapeutic targets, and holds promise for detecting cognitive decline in Alzheimer's disease.
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http://dx.doi.org/10.1016/j.dadm.2019.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880140PMC
December 2019

Role of D3 dopamine receptors in modulating neuroanatomical changes in response to antipsychotic administration.

Sci Rep 2019 05 24;9(1):7850. Epub 2019 May 24.

Integrated Program in Neuroscience, McGill University, Montreal, Quebec, H3A2B4, Canada.

Clinical research has shown that chronic antipsychotic drug (APD) treatment further decreases cortical gray matter and hippocampus volume, and increases striatal and ventricular volume in patients with schizophrenia. D2-like receptor blockade is necessary for clinical efficacy of the drugs, and may be responsible for inducing these volume changes. However, the role of other D2-like receptors, such as D3, remains unclear. Following our previous work, we undertook a longitudinal study to examine the effects of chronic (9-week) typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs on the neuroanatomy of wild-type (WT) and dopamine D3-knockout (D3KO) mice using magnetic resonance imaging (MRI) and histological assessments in a sub-region of the anterior cingulate cortex (the prelimbic [PL] area) and striatum. D3KO mice had larger striatal volume prior to APD administration, coupled with increased glial and neuronal cell density. Chronic HAL administration increased striatal volume in both WT and D3KO mice, and reduced PL area volume in D3KO mice both at trend level. CLZ increased volume of the PL area of WT mice at trend level, but decreased D3KO PL area glial cell density. Both typical and atypical APD administration induced neuroanatomical remodeling of regions rich in D3 receptor expression, and typically altered in schizophrenia. Our findings provide novel insights on the role of D3 receptors in structural changes observed following APD administration in clinical populations.
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http://dx.doi.org/10.1038/s41598-019-43955-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534671PMC
May 2019

Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder: In Vivo Positron Emission Tomography and Postmortem Evidence.

JAMA Psychiatry 2019 08;76(8):854-861

Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.

Importance: Major depressive disorder (MDD) might involve dopamine (DA) reductions. The DA transporter (DAT) regulates DA clearance and neurotransmission and is sensitive to DA levels, with preclinical studies (including those involving inescapable stressors) showing that DAT density decreases when DA signaling is reduced. Despite preclinical data, evidence of reduced DAT in MDD is inconclusive.

Objective: Using a highly selective DAT positron emission tomography (PET) tracer ([11C] altropane), DAT availability was probed in individuals with MDD who were not taking medication. Levels of DAT expression were also evaluated in postmortem tissues from donors with MDD who died by suicide.

Design, Setting, And Participants: This cross-sectional PET study was conducted at McLean Hospital (Belmont, Massachusetts) and Massachusetts General Hospital (Boston) and enrolled consecutive individuals with MDD who were not taking medication and demographically matched healthy controls between January 2012 and March 2014. Brain tissues were obtained from the Douglas-Bell Canada Brain Bank. For the PET component, 25 individuals with current MDD who were not taking medication and 23 healthy controls recruited from McLean Hospital were included (all provided usable data). For the postmortem component, 15 individuals with depression and 14 healthy controls were considered.

Intervention: PET scan.

Main Outcomes And Measures: Striatal and midbrain DAT binding potential was assessed. For the postmortem component, tyrosine hydroxylase and DAT levels were evaluated using Western blots.

Results: Compared with 23 healthy controls (13 women [56.5%]; mean [SD] age, 26.49 [7.26] years), 25 individuals with MDD (19 women [76.0%]; mean [SD] age, 26.52 [5.92] years) showed significantly lower in vivo DAT availability in the bilateral putamen and ventral tegmental area (Cohen d range, -0.62 to -0.71), and both reductions were exacerbated with increasing numbers of depressive episodes. Unlike healthy controls, the MDD group failed to show an age-associated reduction in striatal DAT availability, with young individuals with MDD being indistinguishable from older healthy controls. Moreover, DAT availability in the ventral tegmental area was lowest in individuals with MDD who reported feeling trapped in stressful circumstances. Lower DAT levels (and tyrosine hydroxylase) in the putamen of MDD compared with healthy controls were replicated in postmortem analyses (Cohen d range, -0.92 to -1.15).

Conclusions And Relevance: Major depressive disorder, particularly with recurring episodes, is characterized by decreased striatal DAT expression, which might reflect a compensatory downregulation due to low DA signaling within mesolimbic pathways.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.0801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495358PMC
August 2019

Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons.

Am J Hum Genet 2019 05 25;104(5):815-834. Epub 2019 Apr 25.

Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, WC1N 3BG London, UK.

We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.
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http://dx.doi.org/10.1016/j.ajhg.2019.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6507050PMC
May 2019

MIC-MAC: An automated pipeline for high-throughput characterization and classification of three-dimensional microglia morphologies in mouse and human postmortem brain samples.

Glia 2019 08 14;67(8):1496-1509. Epub 2019 Apr 14.

Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg.

The phenotypic changes of microglia in brain diseases are particularly diverse and their role in disease progression, beneficial, or detrimental, is still elusive. High-throughput molecular approaches such as single-cell RNA-sequencing can now resolve the high heterogeneity in microglia population for a specific physiological condition, however, the relation between the different microglial signatures and their surrounding brain microenvironment is barely understood. Thus, better tools to characterize the phenotypic variations of microglia in situ are needed, particularly for human brain postmortem samples analysis. To address this challenge, we developed MIC-MAC, a Microglia and Immune Cells Morphologies Analyser and Classifier pipeline that semiautomatically segments, extracts, and classifies all microglia and immune cells labeled in large three-dimensional (3D) confocal image stacks of mouse and human brain samples. Our imaging-based approach enables automatic 3D-morphology characterization and classification of thousands of individual microglia in situ and revealed species- and disease-specific morphological phenotypes in mouse aging, human Alzheimer's disease, and dementia with Lewy Bodie's samples. MIC-MAC is a precision diagnostic tool that allows a rapid, unbiased, and large-scale analysis of microglia morphological states in mouse models and patient brain samples.
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http://dx.doi.org/10.1002/glia.23623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617786PMC
August 2019

Astrocytic Epoxyeicosatrienoic Acid Signaling in the Medial Prefrontal Cortex Modulates Depressive-like Behaviors.

J Neurosci 2019 06 22;39(23):4606-4623. Epub 2019 Mar 22.

Institute of Mental Health, Southern Medical University, Guangzhou 510515, China,

Major depressive disorder is the most common mental illness. Mounting evidence indicates that astrocytes play a crucial role in the pathophysiology of depression; however, the underlying molecular mechanisms remain elusive. Compared with other neuronal cell types, astrocytes are enriched for arachidonic acid metabolism. Herein, we observed brain-region-specific alterations of epoxyeicosatrienoic acid (EET) signaling, which is an arachidonic acid metabolic pathway, in both a mouse model of depression and postmortem samples from patients with depression. The enzymatic activity of soluble epoxide hydrolase (sEH), the key enzyme in EET signaling, was selectively increased in the mPFC of susceptible mice after chronic social defeated stress and was negatively correlated with the social interaction ratio, which is an indicator of depressive-like behavior. The specific deletion of (encode sEH) in adult astrocytes induced resilience to stress, whereas the impaired EET signaling in the mPFC evoked depressive-like behaviors in response to stress. sEH was mainly expressed on lysosomes of astrocytes. Using pharmacological and genetic approaches performed on C57BL/6J background adult male mice, we found that EET signaling modulated astrocytic ATP release and Moreover, astrocytic ATP release was required for the antidepressant-like effect of deletion in adult astrocytes. In addition, sEH inhibitors produced rapid antidepressant-like effects in multiple animal models of depression, including chronic social defeated stress and chronic mild stress. Together, our results highlight that EET signaling in astrocytes in the mPFC is essential for behavioral adaptation in response to psychiatric stress. Astrocytes, the most abundant glial cells of the brain, play a vital role in the pathophysiology of depression. Astrocytes secrete adenosine ATP, which modulates depressive-like behaviors. Notably, astrocytes are enriched for arachidonic acid metabolism. In the present study, we explored the hypothesis that epoxyeicosatrienoic acid signaling, an arachidonic acid metabolic pathway, modulates astrocytic ATP release and the expression of depressive-like behaviors. Our work demonstrated that epoxyeicosatrienoic acid signaling in astrocytes in the mPFC is essential for behavioral homeostatic adaptation in response to stress, and the extent of astrocyte functioning is greater than expected based on earlier reports.
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http://dx.doi.org/10.1523/JNEUROSCI.3069-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554635PMC
June 2019
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