Characterizing the transcriptional and neuro-immune consequences of loss of high-confidence bipolar disorder risk gene KDM5B

The National Institute of Mental Health (NIMH) awarded The Broad Institute of MIT and Harvard a $475,388 Project Grant under the Mental Health Research Grants program (CFDA 93.242) to conduct basic neuroscience research investigating the transcriptional and neuro-immune consequences of KDM5B loss in bipolar disorder (BD). The award, initiated June 16, 2025, and extending through June 15, 2027, supports a two-year research initiative examining how genetic predisposition combined with environmental stressors contributes to BD onset. The Broad Institute will deliver comprehensive research products including behavioral assessments of genetically modified mice, transcriptomic analysis characterizing gene expression changes in response to stress, and neuro-immune profiling of microglia-derived cytokine expression and synaptic phagocytosis processes.

This research advances the field's understanding of BD mechanisms by testing the hypothesis that heterozygous loss of KDM5B, a histone demethylase involved in immune regulation identified as a substantial BD risk factor, increases stress susceptibility and triggers abnormal gene expression and immune responses leading to synaptic dysregulation. Deliverables encompass behavioral phenotyping of wild-type and KDM5B mutant mice under basal and stress-induced conditions, transcriptomic datasets from tissue samples, and characterized microglia cytokine profiles from both tissue lysates and isolated microglia populations. These research products directly support NIMH's mission to advance understanding of mental illness etiology and treatment through rigorous scientific inquiry into fundamental disease mechanisms.

Abstract

Characterizing the transcriptional and neuro-immune consequences of loss of high-confidence bipolar disorder risk gene KDM5B. Bipolar disorder (BD) is a prevalent psychiatric condition affecting approximately 5.7 million individuals in the united states. The two-HIT hypothesis posits that a combination of genetic predisposition (first HIT) and environmental stressors (second HIT) can trigger the onset of disorders such as BD. The bipolar exome (bipex) consortium has identified KDM5B, a gene coding for a histone demethylase involved in immune regulation, as a substantial risk factor for bipolar disorder, suggesting its mutation as a potential first HIT. Stress is a major risk factor for BD, elevating glucocorticoid 'stress' hormones, which, in turn, trigger immune responses. Chronic stress can drive microglia into reactive states, resulting in activity-dependent synaptic remodeling in key brain regions, which include the release of immunomodulatory factors and synaptic pruning, making IT a relevant second HIT for altering brain function. We hypothesize that mice with heterozygous loss of KDM5B are more susceptible to stress, and present abnormal gene expression and neuro-immune responses that will lead to synaptic dysregulation. Our specific aims are: 1 - to investigate the impact of stress on behavior and gene transcription of WT and KDM5B heterozygous mice, and 2 - to characterize the neuro-immune responses in KDM5B+/- mice that can influence synaptic phagocytosis. For aim 1, we will assess behavioral patterns that could be altered in KDM5B+/- mice under basal and stress-induced conditions, and determine the transcriptomic changes in KDM5B mutant mice and wild-type controls in response to stress. For aim 2, we will profile microglia-produced cytokine expression in tissue lysates and isolated microglia, and characterize stress-related engulfment of synaptic markers by microglia. Our methodology involves subjecting KDM5B+/- and wild-type mice to a chronic unpredictable stress (CUS) paradigm followed by motion sequencing (moseq) behavioral analysis to determine the behavioral susceptibility of KDM5B+/- mice to stress. For molecular analyses, we will use single-cell RNA sequencing to elucidate transcriptomic changes within microglia and other non-neuronal and neuronal cell populations following loss of KDM5B, which as a histone demethylase is known to be involved in gene regulation. Proteome profiler mouse cytokine array assays will be used to examine alterations in soluble proteins released by microglia. Additionally, feast (flow cytometric engulfment assay for specific target proteins) analysis will detect synaptic pruning by microglia in a single-cell resolution manner. The insights gained by this proposal will enhance our understanding of neuro-immune interactions under stress conditions and provide insight into the basic function of BD risk gene KDM5B.