Natalie Matosin

Major depressive disorder (MDD) involves frontal cortical dysfunction, with emerging evidence implicating gliovascular and immune mechanisms, yet its transcriptional signatures across subregions, cell-types, and molecular layers remain poorly defined. Here, we integrated bulk-tissue RNA-seq data from dlPFC, mPFC, and dACC (n = 286) to identify a conserved core transcriptional profile, anchored in downregulated interneuron markers, and upregulated immune and vascular genes, spatially enriched in leptomeninges and white matter. Concordantly, multiomic factor analysis revealed immune activation, stress-response, and accelerated aging in MDD. Analysis of snRNA-seq data from dlPFC, mPFC, and oFC (863,511 nuclei; n = 204) revealed most pronounced MDD signatures in excitatory neurons, accompanied by coordinated disruption of glucocorticoid receptor machinery across cell-types, including FKBP5 upregulation. Glial, immune, and perivascular populations exhibited signatures of oxidative stress, ECM remodeling, and reduced neuronal support, and greater concordance with bulk-tissue MDD signals than neurons. A global reduction in cell-to-cell communications in MDD revealed a shift from homeostatic neuronal signaling toward endothelial and myelination-associated pathways. Ephrin-Eph signaling was consistently dysregulated, implicating disrupted axonal guidance, synaptic remodeling, and neurovascular integrity. Notably, MDD signatures were shared between MDD-only and PTSD comorbid cases at bulk-tissue analyses, while diverging at single-cell resolution. Together, these findings reframe MDD as a distributed frontal cortex disorder, driven by disrupted neuroglial and neurovascular communication.

Bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia share genetic architecture, yet their molecular mechanisms remain elusive. Both common and rare genetic variants contribute to neural dysfunction, impacting cognition and behavior. This study investigates the molecular effects of genetic variants on human cortical single-cell types using a single-exon analysis approach. Integrating exon-level eQTLs (common variants influencing exon expression) and joint exon eQT-Scores (combining polygenic risk scores with exon-level gene expression) from a postmortem psychiatric cohort (BD = 15, MDD = 24, schizophrenia = 68, controls = 62) with schizophrenia-focused rare variant data from the SCHEMA consortium, we identified 110 core genes enriched in pathways including circadian entrainment (FDR = 0.02), cortisol synthesis and secretion (FDR = 0.026), and dopaminergic synapse (FDR = 0.038). Additional enriched pathways included hormone signaling (FDRs < 0.0298, including insulin, GnRH, aldosterone, and growth hormone pathways) and, notably, adrenergic signaling in cardiomyocytes (FDR = 0.0028). These pathways highlight shared molecular mechanisms in the three disorders. Single-nuclei RNA sequencing data from three cortical regions revealed that these core set genes are predominantly expressed in excitatory neuron layers 2–6 of the dorsolateral prefrontal cortex, linking molecular changes to cell types involved in cognitive dysfunction. Our results demonstrate the power of integrating multimodal genetic and transcriptomic data at the exon level. This approach moves beyond symptom-based diagnoses toward molecular classifications, identifying potential therapeutic targets for psychiatric disorders.

Psychiatric disorders like schizophrenia, bipolar disorder, and major depressive disorder exhibit substantial genetic and clinical overlap. However, their molecular architecture remains elusive due to their polygenic nature and complex brain cell interactions. We integrated clinical data with genetic susceptibility to investigate gene expression and chromatin accessibility in the orbitofrontal cortex of 92 postmortem human brain samples at the single-nucleus (sn) level. Using snRNA-seq and snATAC-seq, we analyzed ~800,000 and 400,000 nuclei, respectively. We observed cell-type–specific dysregulation related to clinical diagnosis and genetic risk. Dysregulation in gene expression and chromatin accessibility associated with diagnosis was pronounced in excitatory neurons. Conversely, genetic risk predominantly affected glial and endothelial cells. Notably, INO80E and HCN2 genes exhibited dysregulation in excitatory neurons’ superficial layers 2/3 influenced by schizophrenia polygenic risk. This study unveils the complex genetic and epigenetic landscape of psychiatric disorders, emphasizing the importance of cell-type–specific analyses in understanding their pathogenesis and contrasting genetic predisposition with clinical diagnosis.

An increasingly compelling body of literature indicates the glucocorticoid receptor cochaperone FK506-binding protein 51 (FKBP51) is a promising target for novel psychiatric therapeutics. However, the mechanisms regulating the corresponding FKBP5 gene directly in the human brain remain largely unknown yet are needed to facilitate the development of precise mechanism-based treatment approaches. Here, we examined FKBP5 DNA methylation patterns in postmortem human brain samples from the dorsolateral prefrontal cortex of individuals who lived with a major psychiatric disorder (schizophrenia, major depression, or bipolar disorder; n=329) and controls n=231. We identified that cytosine-phosphate-guanine-dinucleotide (CpG) specific FKBP5 DNA methylation is altered in psychiatric disorders across the FKBP5 locus, and that these changes are differentially associated with age and genotype (rs1360780 CC vs CT/TT). Individuals with schizophrenia had significantly lower levels of DNA methylation in the proximal enhancer of FKBP5 , which also negatively correlated with FKBP5 gene expression. These changes were also associated with predicted glucocorticoid response elements (GREs) in the proximal enhancer, but not other transcription factor binding sites. This evidence supports that in the human cortex, FKBP5 DNA methylation is associated with both genetic and ageing effects, and that the associations between these factors vary at a diagnosis-specific level in psychopathology. This may have implications for developing FKBP5 -targeted therapeutics and defining a subgroup of patients who will benefit from such treatments.

Astrocytes are a brain cell type vulnerable to the effects of stress and the development of psychiatric-like phenotypes in animals, yet how this translates to humans is unclear. Here, we probed the diversity of ∼145,000 total human cortical astrocytes with single nucleus and spatial transcriptomics, showing that human astrocytes comprise a molecularly and anatomically diverse cell population. In individuals with psychiatric disorders and high adversity exposure, we identified distinct alterations to glutamate-related synaptic functions, supported by histological quantification of >20,000 astrocytes. Early-life adversity exposure produced more pronounced cellular changes than adversity experienced later in life, and female cases displayed stronger transcriptomic associations than males with adversity exposure. Human pluripotent stem cell-derived astrocytes from both two- and three-dimensional models confirmed that glutamate signalling is directly impacted by glucocorticoid activation. Our findings highlight astrocytes as crucial players in how exposure to severe adversity raises risk to psychopathology and position them as strategic pharmacological targets for future intervention strategies.

Familial Alzheimer’s disease (FAD) can be caused by mutations in PSEN1 that encode presenilin-1, a component of the gamma-secretase complex that cleaves amyloid precursor protein. Alterations in calcium (Ca²⁺) homeostasis and glutamate signaling are implicated in the pathogenesis of FAD; however, it has been difficult to assess in humans whether or not these phenotypes are the result of amyloid or tau pathology. This study aimed to assess the early calcium and glutamate phenotypes of FAD by measuring the Ca²⁺ response of induced pluripotent stem cell (iPSC)-derived neurons bearing PSEN1 mutations to glutamate and the ionotropic glutamate receptor agonists NMDA, AMPA, and kainate compared to isogenic control and healthy lines. The data show that in early neurons, even in the absence of amyloid and tau phenotypes, FAD neurons exhibit increased Ca²⁺ responses to glutamate and AMPA, but not NMDA or kainate. Together, this suggests that PSEN1 mutations alter Ca²⁺ and glutamate signaling as an early phenotype of FAD.