Autism-specific spliceosomal transcriptomic signatures in prefrontal cortex contrasted with bipolar disorder.

Multiomic single-nucleus profiling reveals cell-type-specific epigenetic and transcriptional dysregulation in major depressive disorder brain

Abstract Objective Major depressive disorder (MDD) is a leading global cause of disability, marked by persistent mood disturbances, cognitive deficits, and changes in prefrontal cortex neural circuitry. In this study, we aimed to define cell-type-specific molecular and regulatory mechanisms underlying MDD by mapping gene-expression and chromatin-accessibility changes in the dorsolateral prefrontal cortex (PFC) (dlPFC). Methods Postmortem dlPFC (BA9) tissue from 7 MDD and 8 well-matched controls was analyzed using 10× Genomics snRNA-seq and paired ATAC+RNA multiome sequencing. Sequencing data were processed with Cell Ranger pipelines, nuclei were filtered for quality and doublets/debris, and datasets were integrated and clustered using Seurat/Signac packages. Differential gene expression, chromatin accessibility, and transcription factor motif activity were tested between MDD and controls within each cell type, followed by peak-to-gene linkage and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and PsyGeNET enrichment to interpret dysregulated regulatory mechanisms. Results A total of 20 distinct clusters encompassing major neuronal and non-neuronal populations were identified. Differential analyses uncovered extensive cell type-specific changes in chromatin accessibility and gene expression, particularly within excitatory layer 5/6 and inhibitory Pvalb neurons, as well as glial and vascular populations. Functional enrichment indicated dysregulation of synaptic organization, neurotransmission, myelination, stress-response, and immune-regulatory pathways across neuronal and non-neuronal cells. Notably, glucocorticoid-responsive transcription factors NR3C1/NR3C2 exhibited conserved regulatory networks implicating stress signaling in MDD pathophysiology. Conclusions Together, these findings provide a comprehensive single-nucleus atlas of gene regulation in the MDD PFC, highlighting coordinated dysfunction across neurons, glia, and vascular cells.

Identification of EIF4A1 as a candidate molecular indicator of autism spectrum disorder using integrative bioinformatic and biological methods.

This study integrated mRNA expression profiles from five post-mortem brain tissue GEO datasets to identify ASD-associated genes and found that EIF4A1 mRNA expression was significantly elevated in ASD subjects and rescued by treatment with the antipsychotics olanzapine or risperidone.

Transcription-protein dissociation reveals disrupted cellular stress pathways in the prefrontal cortex of depression and schizophrenia subjects

Major depressive disorder (MDD) and schizophrenia (SCZ) are severe psychiatric disorders, the molecular mechanisms of which remain incompletely understood. Increasing evidence implicates neuroinflammatory signaling, autophagy dysregulation, and unfolded protein response (UPR) alterations in their pathophysiology. Here, we analyzed dorsolateral prefrontal cortex (DLPFC) samples from postmortem human brains of 28 MDD subjects, 28 SCZ subjects, and 28 matched controls. Gene expression levels of key inflammatory, autophagy, and UPR-related markers were assessed by RT-qPCR, while selected proteins were quantified by Western blot and ELISA. Logistic and linear regression models were applied to evaluate disease-associated alterations and the influence of sex, age, and cause of death. Transcriptional analyses revealed pathway-specific alterations in both disorders, with IRE1α emerging as the most consistently upregulated marker across MDD and SCZ. Sex-stratified analyses indicated that risk-associated transcriptional changes were more prominent in men with MDD, whereas women with SCZ showed broader transcriptional alterations. Age-related effects were mainly detected at the mRNA level, particularly in autophagy-related genes. In contrast, protein analyses showed a generalized downregulation of several inflammatory (AIM2, NLRP3), autophagy (ATG7, mTOR, RAB5A), and UPR-related (IRE1α) proteins in both disorders. In SCZ subjects who died by suicide, increased IL18, CASPASE-5, and IRE1α transcription, together with increased CASPASE-8 protein levels, suggested enhanced inflammatory and stress-related signaling. Overall, these findings reveal a marked transcription-protein dissociation in key cellular stress pathways in the DLPFC of MDD and SCZ subjects, supporting multilayer regulation of inflammatory, autophagy-related, and UPR responses in the psychiatric brain.

Integrative Multi-Tissue Analysis Identifies Synaptic Gene Networks Specific to Major Depressive Disorder in Women

Cellular transcriptomic signatures underpinning the heterogeneity of depression in Alzheimer's disease

Abstract INTRODUCTION Late‐onset Alzheimer's disease (LOAD) and major depressive disorder (MDD) share genetic etiologies. Here, we investigated brain transcriptomic landscapes to gain insights into shared and divergent molecular and biological etiologies across LOAD and MDD. METHODS Brain single‐nucleus RNA sequencing (snRNA‐seq) datasets from cognitively normal older and young individuals and LOAD patients stratified by comorbid MDD were analyzed to identify differential expressed genes (DEGs). Using cell type–specific DEGs we performed biological pathway and intercellular‐communication networks analyses. We investigated shared DEGs across MDD and LOAD cohorts and sex‐specific DEGs. Results were validated by comparison with four transcriptomic and proteomic studies of MDD and depression. RESULTS MDD‐associated dysregulated genes and pathways were shared between LOAD and cognitive‐normal individuals, including JUNB and DUSP1 in glutamatergic neurons, and PRAM1 and SNX9 in microglia. DEGs shared between the MDD and LOAD cohorts included HSPA1A and NDUFB7 in glutamatergic neurons. Sex interaction analysis identified numerous new DEGs in the MDD cohorts, whereas there were ≈5 to 10 times more DEGs in female than in male individuals. LOAD and MDD common microglial pathways included neuronal injury, stress, peroxisome proliferator‐activated receptor (PPAR) signaling and interferon alpha/beta signaling. DISCUSSION LOAD and MDD exhibited common molecular profiles, dysregulated pathways, and cellular communication changes. MDD develops earlier in life, thus, our findings provide a window into early molecular and biological processes preceding LOAD‐onset.

443. Transcriptomic analysis reveals differential mRNA expression in bipolar disorder

Abstract Background Bipolar disorder (BD) is a chronic and debilitating psychiatric illness characterized by recurrent episodes of mania and depression. Despite its high heritability, the underlying molecular mechanisms remain incompletely understood. Gene expression studies, particularly those focusing on total messenger RNA (mRNA), offer a promising avenue for identifying biomarkers and understanding disease pathophysiology. Among available treatments, lithium remains a first-line mood stabilizer with proven efficacy in reducing recurrence and suicide risk in BD patients. However, response to lithium is highly variable, and predictive biomarkers for treatment outcomes are lacking. Investigating total mRNA expression profiles in blood samples from BD patients characterized for lithium response may provide valuable insights into disease mechanisms and treatment response. Aims & Objectives To identify gene expression markers of disease risk and of response to lithium treatment in bipolar disorder. Method RNA sequencing was performed in a sample of 90 Caucasian patients with a diagnosis of BD type I or BD type II according to DSM-5 and 59 non-psychiatric controls with no personal or familial history of psychiatric disorders. Participants were recruited at the Unit of Clinical Pharmacology and the Unit of Clinical Psychiatry of the University of Cagliari and University Hospital Agency of Cagliari, and at the Psychiatric Hospital “Villa Santa Chiara”, Verona (Italy). For a subgroup of patients (n = 58) response to long-term lithium treatment was characterized with the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder scale (Alda scale). Total RNA was extracted from fasting peripheral venous blood samples. Library preparation and bulk RNA sequencing was performed using the Illumina Stranded Total RNA Prep, and paired-end sequencing was performed on a NextSeq 2000 platform (Illumina). After quality control, raw data were processed with the rnaseq nf-core pipeline, alignment with the reference genome (GRCh38) was performed with STAR, while gene expression levels were estimated with RSEM. Identification of differentially expressed genes (DEG) between patients and controls and responders and non-responders to lithium, adjusting for age and sex, was conducted with DESeq2. Results were adjusted for multiple testing based on false discovery rate (FDR) and an adjusted p-value < 0.05 was considered significant. Results We identified 37 DEGs between patients with BD and controls with an adjusted p-value < 0.05, of which 19 were upregulated and 18 downregulated in patients. DEG significant after multiple testing correction are reported in Table 1. DEG were enriched for the protein folding chaperone molecular function GO term (enrichment ratio: 28.79, p = 0.0002, FDR = 0.041, DNAJB1, HSP90AA1 and HSPH1). No DEG was significantly associated with lithium response after multiple testing correction. However, GO analyses on the nominally significant genes showed a significant enrichment for toll-like receptor binding molecular function GO term. Discussion & Conclusions Our study suggests that BD patients present significant differences in gene expression patterns compared to healthy controls. Pathway analyses suggest that protein misfolding and endoplasmic reticulum alterations could be implicated in the pathophysiology of BD, while response to lithium might be related to modulation of inflammatory response through toll-like receptor biding.