@article{pmid39695100,

title = {Exploring PDE5A upregulation in bipolar disorder: insights from single-nucleus RNA sequencing of human basal ganglia},

author = {Zhixin Bai and Peilong Li and Xu Gao and Gaoyu Zu and Andrew Jiang and Keting Wu and Naguib Mechawar and Gustavo Turecki and Klaus Lehnert and Russell G Snell and Jin Zhou and Jia Hu and Bingbing Yan and Liang Chen and Wensheng Li and You Chen and Shuai Liu and Ying Zhu and Linya You},

doi = {10.1038/s41398-024-03202-5},

issn = {2158-3188},

year  = {2024},

date = {2024-12-01},

journal = {Transl Psychiatry},

volume = {14},

number = {1},

pages = {494},

abstract = {Basal ganglia is proposed to mediate symptoms underlying bipolar disorder (BD). To understand the cell type-specific gene expression and network changes of BD basal ganglia, we performed single-nucleus RNA sequencing of 30,752 nuclei from caudate, putamen, globus pallidus, and substantia nigra of control human postmortem brain and 24,672 nuclei from BD brain. Differential expression analysis revealed major difference lying in caudate, with BD medium spiny neurons (MSNs) expressing significantly higher PDE5A, a cGMP-specific phosphodiesterase. Gene co-expression analysis (WGCNA) showed a strong correlation of caudate MSNs and gene module green, with a PDE5A-containing hub gene network. Gene regulatory network analysis (SCENIC) indicated key regulons among different cell types and basal ganglia regions, with downstream targets of key transcriptional factors showing overlapping genes such as PDEs. Upregulation of PDE5A was further validated in 7 pairs of control and BD caudate sections. Overexpression of PDE5A in primary cultured lateral ganglion eminence-derived striatal neurons led to decreased dendrite complexity, increased apoptosis, and enhanced neuronal excitability and membrane resistance. This effect could be rescued by PDE5 specific inhibitor, tadalafil. Overexpression of PDE5A in mouse striatum by stereotaxic injection caused a decreased cGMP level, an increased gene expression profile of neuroinflammation, and BD-like behaviors. Collectively, our findings provided cell type-specific gene expression profile, and indicated a causative role of PDE5A upregulation in BD basal ganglia. This study provides a single-nucleus transcriptomic profile of human control and bipolar disorder (BD) basal ganglia. Differential expression, gene co-expression, and gene regulatory network analyses collectively indicated upregulation of PDE5A in BD caudate medium spiny neurons (MSNs), which was further validated in another cohort of BD brains. The causative role of PDE5A upregulation in BD etiology is supported by the effects of PDE5A overexpression in cultured mouse MSNs in vitro and in adult mouse striatum in vivo. The former led to reduced dendrite complexity, increased apoptosis, and neuronal hyper-excitability, which could be rescued by PDE5 specific inhibitor tadalafil. The latter caused lower cGMP levels, upregulated genes associated with neuroinflammation, and BD-like behaviors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39128570,

title = {Proteomic evidence of depression-associated astrocytic dysfunction in the human male olfactory bulb},

author = {Reza Rahimian and Kelly Perlman and Gohar Fakhfouri and Refilwe Mpai and Vincent R Richard and Christa Hercher and Lucy Penney and Maria Antonietta Davoli and Corina Nagy and René P Zahedi and Christoph H Borchers and Bruno Giros and Gustavo Turecki and Naguib Mechawar},

doi = {10.1016/j.bbi.2024.08.016},

issn = {1090-2139},

year  = {2024},

date = {2024-11-01},

journal = {Brain Behav Immun},

volume = {122},

pages = {110--121},

abstract = {The olfactory bulb (OB), a major structure of the limbic system, has been understudied in human investigations of psychopathologies such as depression. To explore more directly the molecular features of the OB in depression, a global comparative proteome analysis was carried out with human post-mortem OB samples from 11 males having suffered from depression and 12 healthy controls. We identified 188 differentially abundant proteins (with adjusted p < 0.05) between depressed cases and controls. Gene ontology and gene enrichment analyses suggested that these proteins are involved in biological processes including the complement and coagulation cascades. Cell type enrichment analysis displayed a significant reduction in several canonical astrocytic proteins in OBs from depressed patients. Furthermore, using RNA-fluorescence in-situ hybridization, we observed a decrease in the percentage of ALDH1L1 cells expressing canonical astrocytic markers including ALDOC, NFIA, GJA1 (connexin 43) and SLC1A3 (EAAT1). These results are consistent with previous reports of downregulated astrocytic marker expression in other brain regions in depressed patients. We also conducted a comparative phosphoproteomic analysis of OB samples and found a dysregulation of proteins involved in neuronal and astrocytic functions. To determine whether OB astrocytic abnormalities is specific to humans, we also performed proteomics on the OB of socially defeated male mice, a commonly used model of depression. Cell-type specific analysis revealed that in socially defeated animals, the most striking OB protein alterations were associated with oligodendrocyte-lineage cells rather than with astrocytes, highlighting an important species difference. Overall, this study further highlights cerebral astrocytic abnormalities as a consistent feature of depression in humans.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39511452,

title = {Evidence of altered monoamine oxidase B, an astroglia marker, in early psychosis and high-risk state},

author = {Kankana Nisha Aji and Nittha Lalang and Christian Ramos-Jiménez and Reza Rahimian and Naguib Mechawar and Gustavo Turecki and Daniel Chartrand and Isabelle Boileau and Jeffrey H Meyer and Pablo M Rusjan and Romina Mizrahi},

doi = {10.1038/s41380-024-02816-x},

issn = {1476-5578},

year  = {2024},

date = {2024-11-01},

journal = {Mol Psychiatry},

abstract = {A novel radiotracer, [C]SL25.1188, targets monoamine oxidase-B (MAO-B) enzyme, found primarily in astrocytes, which metabolizes monoamines (including dopamine), particularly in subcortical regions. Altered astrocyte function in schizophrenia is supported by convergent evidence from post-mortem, genetic, transcriptomic, peripheral and preclinical findings. We aimed to test whether levels of MAO-B, an index of astrocyte function are low in the living brains of early psychosis and their high-risk states. Thirty-eight participants including antipsychotic-free/minimally exposed clinical participants with first-episode psychosis (FEP), clinical high-risk (CHR) individuals and healthy volunteers (HVs) underwent a 90-min positron emission tomography (PET) scan with [C]SL25.1188, to measure MAO-B V, an index of MAO-B concentration. Participants were excluded if tested positive on urine drug screen (except for cannabis). This study of 14 FEP (mean[SD] age, 25.7[5.7] years; 6 F), 7 CHR (mean[SD] age, 20.9[3.7] years; 4 F) and 17 HV (mean[SD] age, 31.2[13.9] years; 9 F) demonstrated significant group differences in regional MAO-B V (F = 4.56, p = 0.02, Cohen's f = 0.49), controlling for tobacco (F  = 5.37, p = 0.03) and cannabis use (F = 5.11, p = 0.03) with significantly lower MAO-B V in CHR compared to HV (Cohen's d = 0.99). We report a significant cannabis effect on MAO-B V (F = 12.57, p = 0.001, Cohen's f = 0.57), with a significant group-by-cannabis interaction (F = 3.82, p = 0.03, Cohen's f = 0.45), indicating lower MAO-B V in cannabis-using clinical groups. Lower MAO-B V levels were more robust in striatal than cortical regions, in both clinical groups (F = 2.08, p = 0.04, Cohen's f = 0.73) and in cannabis users (F = 6.42, p < 0.001, Cohen's f = 0.91). Lower MAO-B concentration supports astrocyte dysfunction in cannabis-using CHR and FEP clinical populations. Lower MAO-B is consistent with replicated striatal dopamine elevation in psychosis, as well as astrocyte dysfunction in schizophrenia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39384764,

title = {Multi-omics profiling of DNA methylation and gene expression alterations in human cocaine use disorder},

author = {Eric Zillich and Hanna Belschner and Diana Avetyan and Diego Andrade-Brito and José Jaime Martínez-Magaña and Josef Frank and Naguib Mechawar and Gustavo Turecki and Judit Cabana-Domínguez and Noèlia Fernàndez-Castillo and Bru Cormand and Janitza L Montalvo-Ortiz and Markus M Nöthen and Anita C Hansson and Marcella Rietschel and Rainer Spanagel and Stephanie H Witt and Lea Zillich},

doi = {10.1038/s41398-024-03139-9},

issn = {2158-3188},

year  = {2024},

date = {2024-10-01},

journal = {Transl Psychiatry},

volume = {14},

number = {1},

pages = {428},

abstract = {Structural and functional changes of the brain are assumed to contribute to excessive cocaine intake, craving, and relapse in cocaine use disorder (CUD). Epigenetic and transcriptional changes were hypothesized as a molecular basis for CUD-associated brain alterations. Here we performed a multi-omics study of CUD by integrating epigenome-wide methylomic (N = 42) and transcriptomic (N = 25) data from the same individuals using postmortem brain tissue of Brodmann Area 9 (BA9). Of the N = 1 057 differentially expressed genes (p < 0.05), one gene, ZFAND2A, was significantly upregulated in CUD at transcriptome-wide significance (q < 0.05). Differential alternative splicing (AS) analysis revealed N = 98 alternatively spliced transcripts enriched in axon and dendrite extension pathways. Strong convergent overlap in CUD-associated expression deregulation was found between our BA9 cohort and independent replication datasets. Epigenomic, transcriptomic, and AS changes in BA9 converged at two genes, ZBTB4 and INPP5E. In pathway analyses, synaptic signaling, neuron morphogenesis, and fatty acid metabolism emerged as the most prominently deregulated biological processes. Drug repositioning analysis revealed glucocorticoid receptor targeting drugs as most potent in reversing the CUD expression profile. Our study highlights the value of multi-omics approaches for an in-depth molecular characterization and provides insights into the relationship between CUD-associated epigenomic and transcriptomic signatures in the human prefrontal cortex.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39334854,

title = {Perineuronal Net Alterations Following Early-Life Stress: Are Microglia Pulling Some Strings?},

author = {Reza Rahimian and Claudia Belliveau and Sophie Simard and Gustavo Turecki and Naguib Mechawar},

doi = {10.3390/biom14091087},

issn = {2218-273X},

year  = {2024},

date = {2024-08-01},

journal = {Biomolecules},

volume = {14},

number = {9},

abstract = {The extracellular matrix plays a key role in synapse formation and in the modulation of synaptic function in the central nervous system. Recent investigations have revealed that microglia, the resident immune cells of the brain, are involved in extracellular matrix remodeling under both physiological and pathological conditions. Moreover, the dysregulation of both innate immune responses and the extracellular matrix has been documented in stress-related psychopathologies as well as in relation to early-life stress. However, the dynamics of microglial regulation of the ECM and how it can be impacted by early-life adversity have been understudied. This brief review provides an overview of the recent literature on this topic, drawing from both animal model and human post mortem studies. Direct and indirect mechanisms through which microglia may regulate the extracellular matrix-including perineuronal nets-are presented and discussed in light of the interactions with other cell types.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38995945,

title = {Chondroitin sulfate glycan sulfation patterns influence histochemical labeling of perineuronal nets: a comparative study of interregional distribution in human and mouse brain},

author = {Claudia Belliveau and Stéphanie Théberge and Stefanie Netto and Reza Rahimian and Gohar Fakhfouri and Clémentine Hosdey and Maria Antonietta Davoli and Aarun Hendrickson and Kathryn Hao and Bruno Giros and Gustavo Turecki and Kimberly M Alonge and Naguib Mechawar},

doi = {10.1093/glycob/cwae049},

issn = {1460-2423},

year  = {2024},

date = {2024-06-01},

journal = {Glycobiology},

volume = {34},

number = {8},

abstract = {Perineuronal nets (PNNs) are a condensed subtype of extracellular matrix that form a net-like coverings around certain neurons in the brain. PNNs are primarily composed of chondroitin sulfate (CS) proteoglycans from the lectican family that consist of CS-glycosaminoglycan side chains attached to a core protein. CS disaccharides can exist in various isoforms with different sulfation patterns. Literature suggests that CS disaccharide sulfation patterns can influence the function of PNNs as well as their labeling. This study was conducted to characterize such interregional CS disaccharide sulfation pattern differences in adult human (n = 81) and mouse (n = 19) brains. Liquid chromatography tandem mass spectrometry was used to quantify five different CS disaccharide sulfation patterns, which were then compared to immunolabeling of PNNs using Wisteria Floribunda Lectin (WFL) to identify CS-glycosaminoglycans and anti-aggrecan to identify CS proteoglycans. In healthy brains, significant regional and species-specific differences in CS disaccharide sulfation and single versus double-labeling pattern were identified. A secondary analysis to investigate how early-life stress impacts these PNN features discovered that although early-life stress increases WFL+ PNN density, the CS-glycosaminoglycan sulfation code and single versus double PNN-labeling distributions remained unaffected in both species. These results underscore PNN complexity in traditional research, emphasizing the need to consider their heterogeneity in future experiments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38948769,

title = {Chondroitin sulfate glycan sulfation patterns influence histochemical labeling of perineuronal nets: a comparative study of interregional distribution in human and mouse brain},

author = {Claudia Belliveau and Stéphanie Théberge and Stefanie Netto and Reza Rahimian and Gohar Fakhfouri and Clémentine Hosdey and Maria Antonietta Davoli and Aarun Hendrickson and Kathryn Hao and Bruno Giros and Gustavo Turecki and Kimberly M Alonge and Naguib Mechawar},

doi = {10.1101/2024.02.09.579711},

issn = {2692-8205},

year  = {2024},

date = {2024-06-01},

journal = {bioRxiv},

abstract = {Perineuronal nets (PNNs) are a condensed subtype of extracellular matrix that form a net-like coverings around certain neurons in the brain. PNNs are primarily composed of chondroitin sulfate (CS) proteoglycans from the lectican family that consist of CS-glycosaminoglycan (CS-GAG) side chains attached to a core protein. CS disaccharides can exist in various isoforms with different sulfation patterns. Literature suggests that CS disaccharide sulfation patterns can influence the function of PNNs as well as their labeling. This study was conducted to characterize such interregional CS disaccharide sulfation pattern differences in adult human (N = 81) and mouse (N = 19) brains. Liquid chromatography tandem mass spectrometry was used to quantify five different CS disaccharide sulfation patterns, which were then compared to immunolabeling of PNNs using  (WFL) to identify CS-GAGs and anti-aggrecan to identify CS proteoglycans. In healthy brains, significant regional and species-specific differences in CS disaccharide sulfation and single versus double-labeling pattern were identified. A secondary analysis to investigate how early-life stress (ELS) impacts these PNN features discovered that although ELS increases WFL+ PNN density, the CS-GAG sulfation code and single versus double PNN-labeling distributions remained unaffected in both species. These results underscore PNN complexity in traditional research, emphasizing the need to consider their heterogeneity in future experiments.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38631765,

title = {MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study},

author = {Rebecca R Valentino and William J Scotton and Shanu F Roemer and Tammaryn Lashley and Michael G Heckman and Maryam Shoai and Alejandro Martinez-Carrasco and Nicole Tamvaka and Ronald L Walton and Matthew C Baker and Hannah L Macpherson and Raquel Real and Alexandra I Soto-Beasley and Kin Mok and Tamas Revesz and Elizabeth A Christopher and Michael DeTure and William W Seeley and Edward B Lee and Matthew P Frosch and Laura Molina-Porcel and Tamar Gefen and Javier Redding-Ochoa and Bernardino Ghetti and Andrew C Robinson and Christopher Kobylecki and James B Rowe and Thomas G Beach and Andrew F Teich and Julia L Keith and Istvan Bodi and Glenda M Halliday and Marla Gearing and Thomas Arzberger and Christopher M Morris and Charles L White and Naguib Mechawar and Susana Boluda and Ian R MacKenzie and Catriona McLean and Matthew D Cykowski and Shih-Hsiu J Wang and Caroline Graff and Rashed M Nagra and Gabor G Kovacs and Giorgio Giaccone and Manuela Neumann and Lee-Cyn Ang and Agostinho Carvalho and Huw R Morris and Rosa Rademakers and John A Hardy and Dennis W Dickson and Jonathan D Rohrer and Owen A Ross and },

doi = {10.1016/S1474-4422(24)00083-8},

issn = {1474-4465},

year  = {2024},

date = {2024-05-01},

journal = {Lancet Neurol},

volume = {23},

number = {5},

pages = {487--499},

abstract = {BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration.nnMETHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and β coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype.nnFINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (β -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (β 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (β 2·66 [0·63 to 4·70], p=0·011), H1i (β -3·66 [-6·83 to -0·48], p=0·025), and H1u (β -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (β -0·57 [-1·07 to -0·07], p=0·026).nnINTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies.nnFUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38757781,

title = {Adult Hippocampal Neurogenesis in the Human Brain: Updates, Challenges, and Perspectives},

author = {Sophie Simard and Natalie Matosin and Naguib Mechawar},

doi = {10.1177/10738584241252581},

issn = {1089-4098},

year  = {2024},

date = {2024-05-01},

journal = {Neuroscientist},

pages = {10738584241252581},

abstract = {The existence of neurogenesis in the adult human hippocampus has been under considerable debate within the past three decades due to the diverging conclusions originating mostly from immunohistochemistry studies. While some of these reports conclude that hippocampal neurogenesis in humans occurs throughout physiologic aging, others indicate that this phenomenon ends by early childhood. More recently, some groups have adopted next-generation sequencing technologies to characterize with more acuity the extent of this phenomenon in humans. Here, we review the current state of research on adult hippocampal neurogenesis in the human brain with an emphasis on the challenges and limitations of using immunohistochemistry and next-generation sequencing technologies for its study.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38760318,

title = {Parvalbumin interneurons in human ventromedial prefrontal cortex: a comprehensive post-mortem study of myelination and perineuronal nets in neurotypical individuals and depressed suicides with and without a history of child abuse},

author = {Stéphanie Théberge and Claudia Belliveau and Dongyue Xie and Roy Khalaf and Kelly Perlman and Reza Rahimian and Maria Antonietta Davoli and Gustavo Turecki and Naguib Mechawar},

doi = {10.1093/cercor/bhae197},

issn = {1460-2199},

year  = {2024},

date = {2024-05-01},

journal = {Cereb Cortex},

volume = {34},

number = {5},

abstract = {Cortical parvalbumin interneurons (PV+) are major regulators of excitatory/inhibitory information processing, and their maturation is associated with the opening of developmental critical periods (CP). Recent studies reveal that cortical PV+ axons are myelinated, and that myelination along with perineuronal net (PNN) maturation around PV+ cells is associated with the closures of CP. Although PV+ interneurons are susceptible to early-life stress, their relationship between their myelination and PNN coverage remains unexplored. This study compared the fine features of PV+ interneurons in well-characterized human post-mortem ventromedial prefrontal cortex samples (n = 31) from depressed suicides with or without a history of child abuse (CA) and matched controls. In healthy controls, 81% of all sampled PV+ interneurons displayed a myelinated axon, while a subset (66%) of these cells also displayed a PNN, proposing a relationship between both attributes. Intriguingly, a 3-fold increase in the proportion of unmyelinated PV+ interneurons with a PNN was observed in CA victims, along with greater PV-immunofluorescence intensity in myelinated PV+ cells with a PNN. This study, which is the first to provide normative data on myelination and PNNs around PV+ interneurons in human neocortex, sheds further light on the cellular and molecular consequences of early-life adversity on cortical PV+ interneurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38589409,

title = {SNORA69 is up-regulated in the lateral habenula of individuals with major depressive disorder},

author = {Rixing Lin and Haruka Mitsuhashi and Laura M Fiori and Ryan Denniston and El Cherif Ibrahim and Catherine Belzung and Naguib Mechawar and Gustavo Turecki},

doi = {10.1038/s41598-024-58278-2},

issn = {2045-2322},

year  = {2024},

date = {2024-04-01},

journal = {Sci Rep},

volume = {14},

number = {1},

pages = {8258},

abstract = {Major depressive disorder (MDD) is a complex and potentially debilitating illness whose etiology and pathology remains unclear. Non-coding RNAs have been implicated in MDD, where they display differential expression in the brain and the periphery. In this study, we quantified small nucleolar RNA (snoRNA) expression by small RNA sequencing in the lateral habenula (LHb) of individuals with MDD (n = 15) and psychiatrically-healthy controls (n = 15). We uncovered five snoRNAs that exhibited differential expression between MDD and controls (FDR < 0.01). Specifically, SNORA69 showed increased expression in MDD and was technically validated via RT-qPCR. We further investigated the expression of Snora69 in the LHb and peripheral blood of an unpredicted chronic mild stress (UCMS) mouse model of depression. Snora69 was specifically up-regulated in mice that underwent the UCMS paradigm. SNORA69 is known to guide pseudouridylation onto 5.8S and 18S rRNAs. We quantified the relative abundance of pseudouridines on 5.8S and 18S rRNA in human post-mortem LHb samples and found increased abundance of pseudouridines in the MDD group. Overall, our findings indicate the importance of brain snoRNAs in the pathology of MDD. Future studies characterizing SNORA69's role in MDD pathology is warranted.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38457375,

title = {Profiling Small RNA From Brain Extracellular Vesicles in Individuals With Depression},

author = {Pascal Ibrahim and Ryan Denniston and Haruka Mitsuhashi and Jennie Yang and Laura M Fiori and Dariusz Żurawek and Naguib Mechawar and Corina Nagy and Gustavo Turecki},

doi = {10.1093/ijnp/pyae013},

issn = {1469-5111},

year  = {2024},

date = {2024-03-01},

journal = {Int J Neuropsychopharmacol},

volume = {27},

number = {3},

abstract = {BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability with significant mortality risk. Despite progress in our understanding of the etiology of MDD, the underlying molecular changes in the brain remain poorly understood. Extracellular vesicles (EVs) are lipid-bound particles that can reflect the molecular signatures of the tissue of origin. We aimed to optimize a streamlined EV isolation protocol from postmortem brain tissue and determine whether EV RNA cargo, particularly microRNAs (miRNAs), have an MDD-specific profile.nnMETHODS: EVs were isolated from postmortem human brain tissue. Quality was assessed using western blots, transmission electron microscopy, and microfluidic resistive pulse sensing. EV RNA was extracted and sequenced on Illumina platforms. Functional follow-up was performed in silico.nnRESULTS: Quality assessment showed an enrichment of EV markers, as well as a size distribution of 30 to 200 nm in diameter, and no contamination with cellular debris. Small RNA profiling indicated the presence of several RNA biotypes, with miRNAs and transfer RNAs being the most prominent. Exploring miRNA levels between groups revealed decreased expression of miR-92a-3p and miR-129-5p, which was validated by qPCR and was specific to EVs and not seen in bulk tissue. Finally, in silico functional analyses indicate potential roles for these 2 miRNAs in neurotransmission and synaptic plasticity.nnCONCLUSION: We provide a streamlined isolation protocol that yields EVs of high quality that are suitable for molecular follow-up. Our findings warrant future investigations into brain EV miRNA dysregulation in MDD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38150991,

title = {Enhancing HIF-1α-P2X2 signaling in dorsal raphe serotonergic neurons promotes psychological resilience},

author = {Yuan Zhang and Yi-da Pan and Wen-Ying Zheng and Huan-Yu Li and Min-Zhen Zhu and Wen-Jie Ou Yang and Yu Qian and Gustavo Turecki and Naguib Mechawar and Xin-Hong Zhu},

doi = {10.1016/j.redox.2023.103005},

issn = {2213-2317},

year  = {2024},

date = {2024-02-01},

journal = {Redox Biol},

volume = {69},

pages = {103005},

abstract = {Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN neurons as a potential avenue for screening novel therapeutic treatments for MDD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37931511,

title = {Substance P, NPY, CCK and their receptors in five brain regions in major depressive disorder with transcriptomic analysis of locus coeruleus neurons},

author = {Swapnali Barde and Julio Aguila and Wen Zhong and Anna Solarz and Irene Mei and Josee Prud'homme and Miklos Palkovits and Gustavo Turecki and Jan Mulder and Mathias Uhlén and Corina Nagy and Naguib Mechawar and Eva Hedlund and Tomas Hökfelt},

doi = {10.1016/j.euroneuro.2023.09.004},

issn = {1873-7862},

year  = {2024},

date = {2024-01-01},

journal = {Eur Neuropsychopharmacol},

volume = {78},

pages = {54--63},

abstract = {Major depressive disorder (MDD) is a serious disease and a burden to patients, families and society. Rodent experiments and human studies suggest that several neuropeptide systems are involved in mood regulation. The aim of this study is two-fold: (i) to monitor, with qPCR, transcript levels of the substance P/tachykinin (TAC), NPY and CCK systems in bulk samples from control and suicide subjects, targeting five postmortem brain regions including locus coeruleus (LC); and (ii) to analyse expression of neuropeptide family transcripts in LC neurons of 'normal' postmortem brains by using laser capture microdissection with Smart-Seq2 RNA sequencing. qPCR revealed distinct regional expression patterns in male and female controls with higher levels for the TAC system in the dorsal raphe nucleus and LC, versus higher transcripts levels of the NPY and CCK systems in prefrontal cortex. In suicide patients, TAC, TAC receptors and a few NPY family transcript levels were increased mainly in prefrontal cortex and LC. The second study on 'normal' noradrenergic LC neurons revealed expression of transcripts for GAL, NPY, TAC1, CCK, and TACR1 and many other peptides (e.g. Cerebellin4 and CARTPT) and receptors (e.g. Adcyap1R1 and GPR173). These data and our previous results on suicide brains indicates that the tachykinin and galanin systems may be valid targets for developing antidepressant medicines. Moreover, the perturbation of neuropeptide systems in MDD patients, and the detection of further neuropeptide and receptor transcripts in LC, shed new light on signalling in noradrenergic LC neurons and on mechanisms possibly associated with mood disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39414359,

title = {Spatial transcriptomic analysis of adult hippocampal neurogenesis in the human brain},

author = {Sophie Simard and Reza Rahimian and Maria Antonietta Davoli and Stéphanie Théberge and Natalie Matosin and Gustavo Turecki and Corina Nagy and Naguib Mechawar},

doi = {10.1503/jpn.240026},

issn = {1488-2434},

year  = {2024},

date = {2024-01-01},

journal = {J Psychiatry Neurosci},

volume = {49},

number = {5},

pages = {E319--E333},

abstract = {BACKGROUND: Adult hippocampal neurogenesis has been extensively characterized in rodent models, but its existence in humans remains controversial. We sought to assess the phenomenon in postmortem human hippocampal samples by combining spatial transcriptomics and multiplexed fluorescent in situ hybridization.nnMETHODS: We computationally examined the spatial expression of various canonical neurogenesis markers in postmortem dentate gyrus (DG) sections from young and middle-aged sudden-death males. We conducted in situ assessment of markers expressed in neural stem cells, proliferative cells, and immature granule neurons in postmortem DG sections from infant, adolescent, and middle-aged males.nnRESULTS: We examined frozen DG tissue from infant ( = 1, age 2 yr), adolescent ( = 1, age 16 yr), young adult ( = 2, mean age 23.5 yr), and middle-aged ( = 2, mean age 42.5 yr) males, and frozen-fixed DG tissue from middle-aged males ( = 6, mean age 43.5 yr). We detected very few cells expressing neural stem cell and proliferative markers in the human DG from childhood to middle age. However, at all ages, we observed a substantial number of DG cells expressing the immature neuronal marker . Most   cells displayed an inhibitory phenotype, while the remainder were non-committed or excitatory in nature.nnLIMITATIONS: The study was limited by small sample sizes and included samples only from males.nnCONCLUSION: Our findings indicate very low levels of hippocampal neurogenesis throughout life and the existence of a local reserve of plasticity in the adult human hippocampus. Overall, our study provides important insight into the distribution and phenotype of cells expressing neurogenesis markers in the adult human hippocampus.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37822873,

title = {Universal method for the isolation of microvessels from frozen brain tissue: A proof-of-concept multiomic investigation of the neurovasculature},

author = {Marina Wakid and Daniel Almeida and Zahia Aouabed and Reza Rahimian and Maria Antonietta Davoli and Volodymyr Yerko and Elena Leonova-Erko and Vincent Richard and René Zahedi and Christoph Borchers and Gustavo Turecki and Naguib Mechawar},

doi = {10.1016/j.bbih.2023.100684},

issn = {2666-3546},

year  = {2023},

date = {2023-12-01},

journal = {Brain Behav Immun Health},

volume = {34},

pages = {100684},

abstract = {The neurovascular unit, comprised of vascular cell types that collectively regulate cerebral blood flow to meet the needs of coupled neurons, is paramount for the proper function of the central nervous system. The neurovascular unit gatekeeps blood-brain barrier properties, which experiences impairment in several central nervous system diseases associated with neuroinflammation and contributes to pathogenesis. To better understand function and dysfunction at the neurovascular unit and how it may confer inflammatory processes within the brain, isolation and characterization of the neurovascular unit is needed. Here, we describe a singular, standardized protocol to enrich and isolate microvessels from archived snap-frozen human and frozen mouse cerebral cortex using mechanical homogenization and centrifugation-separation that preserves the structural integrity and multicellular composition of microvessel fragments. For the first time, microvessels are isolated from postmortem ventromedial prefrontal cortex tissue and are comprehensively investigated as a structural unit using both RNA sequencing and Liquid Chromatography with tandem mass spectrometry (LC-MS/MS). Both the transcriptome and proteome are obtained and compared, demonstrating that the isolated brain microvessel is a robust model for the NVU and can be used to generate highly informative datasets in both physiological and disease contexts.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37432876,

title = { SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants},

author = {Rixing Lin and Aron Kos and Juan Pablo Lopez and Julien Dine and Laura M Fiori and Jennie Yang and Yair Ben-Efraim and Zahia Aouabed and Pascal Ibrahim and Haruka Mitsuhashi and Tak Pan Wong and El Cherif Ibrahim and Catherine Belzung and Pierre Blier and Faranak Farzan and Benicio N Frey and Raymond W Lam and Roumen Milev and Daniel J Muller and Sagar V Parikh and Claudio Soares and Rudolf Uher and Corina Nagy and Naguib Mechawar and Jane A Foster and Sidney H Kennedy and Alon Chen and Gustavo Turecki},

doi = {10.7554/eLife.85316},

issn = {2050-084X},

year  = {2023},

date = {2023-07-01},

urldate = {2023-07-01},

journal = {Elife},

volume = {12},

abstract = {Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, , was elevated following treatment response. When we increased  levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 () as one of the targets of , which we show is regulated through the accumulation of N-methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37217515,

title = {Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes},

author = {Malosree Maitra and Haruka Mitsuhashi and Reza Rahimian and Anjali Chawla and Jennie Yang and Laura M Fiori and Maria Antonietta Davoli and Kelly Perlman and Zahia Aouabed and Deborah C Mash and Matthew Suderman and Naguib Mechawar and Gustavo Turecki and Corina Nagy},

doi = {10.1038/s41467-023-38530-5},

issn = {2041-1723},

year  = {2023},

date = {2023-05-01},

journal = {Nat Commun},

volume = {14},

number = {1},

pages = {2912},

abstract = {Major depressive disorder (MDD) is a common, heterogenous, and potentially serious psychiatric illness. Diverse brain cell types have been implicated in MDD etiology. Significant sexual differences exist in MDD clinical presentation and outcome, and recent evidence suggests different molecular bases for male and female MDD. We evaluated over 160,000 nuclei from 71 female and male donors, leveraging new and pre-existing single-nucleus RNA-sequencing data from the dorsolateral prefrontal cortex. Cell type specific transcriptome-wide threshold-free MDD-associated gene expression patterns were similar between the sexes, but significant differentially expressed genes (DEGs) diverged. Among 7 broad cell types and 41 clusters evaluated, microglia and parvalbumin interneurons contributed the most DEGs in females, while deep layer excitatory neurons, astrocytes, and oligodendrocyte precursors were the major contributors in males. Further, the Mic1 cluster with 38% of female DEGs and the ExN10_L46 cluster with 53% of male DEGs, stood out in the meta-analysis of both sexes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36729133,

title = {Associations of psychiatric disease and ageing with FKBP5 expression converge on superficial layer neurons of the neocortex},

author = {Natalie Matosin and Janine Arloth and Darina Czamara and Katrina Z Edmond and Malosree Maitra and Anna S Fröhlich and Silvia Martinelli and Dominic Kaul and Rachael Bartlett and Amber R Curry and Nils C Gassen and Kathrin Hafner and Nikola S Müller and Karolina Worf and Ghalia Rehawi and Corina Nagy and Thorhildur Halldorsdottir and Cristiana Cruceanu and Miriam Gagliardi and Nathalie Gerstner and Maik Ködel and Vanessa Murek and Michael J Ziller and Elizabeth Scarr and Ran Tao and Andrew E Jaffe and Thomas Arzberger and Peter Falkai and Joel E Kleinmann and Daniel R Weinberger and Naguib Mechawar and Andrea Schmitt and Brian Dean and Gustavo Turecki and Thomas M Hyde and Elisabeth B Binder},

doi = {10.1007/s00401-023-02541-9},

issn = {1432-0533},

year  = {2023},

date = {2023-04-01},

journal = {Acta Neuropathol},

volume = {145},

number = {4},

pages = {439--459},

abstract = {Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n = 1024) of FKBP5/1, examining neocortical areas (BA9, BA11 and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, ageing and genotype on cortical FKBP5/1 expression including in a cell type-specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established that these disease and ageing effects on FKBP5/1 expression were most pronounced in excitatory superficial layer neurons of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found that this increase in FKBP5 levels may impact on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in superficial layer neurons in BA11. These findings pinpoint a novel cellular and molecular mechanism that has potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}