In a groundbreaking study that redefines our understanding of neuroimmune dynamics, researchers have unveiled the profound effects of CHD8 gene modulation within adult microglia—the brain’s resident immune cells—highlighting striking sex-dependent variations in behavior, morphology, and gene expression. This pioneering investigation into genetically engineered C57BL6 mice demonstrates that manipulating CHD8 expression in microglia, well beyond developmental stages, orchestrates wide-ranging changes that may illuminate new pathways for tackling neuropsychiatric disorders and neuroinflammation.
CHD8, or chromodomain helicase DNA-binding protein 8, has long been recognized for its role in chromatin remodeling and transcriptional regulation, particularly during embryonic brain development. Mutations in CHD8 have been implicated in autism spectrum disorder (ASD) and other neurodevelopmental conditions, primarily through disrupted neural proliferation and differentiation. However, the impact of CHD8 beyond early development—especially within adult microglia, which modulate synaptic remodeling, neuroinflammation, and brain homeostasis—remained controversially underexplored until now.
The research team employed a sophisticated conditional knockdown approach, specifically targeting CHD8 gene expression in mature microglia of adult C57BL6 mice. This precise temporal and cell-type-specific intervention allowed the dissection of CHD8’s role distinct from developmental influences, focusing on how mature immune cells in the brain contribute to behavioral phenotypes and neuropathological hallmarks. The findings revealed that CHD8 knockdown triggered substantial alterations in microglial morphology, including increased ramification and altered cell density—features intimately tied to cellular activation states and neuroimmune surveillance.
Beyond cellular changes, transcriptional profiling of microglia exposed profound shifts in gene networks associated with immune signaling, synaptic modulation, and metabolic pathways. These molecular signatures underscore the multifaceted influence of CHD8 in regulating microglial functional states, potentially affecting synaptic pruning and neuronal circuit stability. Remarkably, the transcriptional response diverged considerably between male and female mice, illuminating a critical sex-dependent dimension in neuroimmune gene regulation.
The behavioral phenotype of CHD8 knockdown mice further corroborated the molecular findings, as distinct male and female aberrations emerged in standard assays exploring anxiety-like behavior, social interaction, and cognitive flexibility. These behavioral discrepancies align with sex-biased prevalence and presentation seen in several neuropsychiatric disorders, suggesting that microglial CHD8 activity may differentially shape male versus female brain function and disease susceptibility. This sex-dependent signature marks a significant advance in deciphering the complexities of neurological sex differences at the immune cell level.
Intriguingly, the morphological adaptations of microglia were not uniform. In males, CHD8 suppression induced a hypertrophic microglial state characterized by enlarged cell bodies and increased process complexity, indicative of heightened surveillance or reactive phenotypes. Females, conversely, exhibited more subtle microglial remodeling but showed distinct expression patterns of genes linked to anti-inflammatory and repair pathways, revealing a nuanced, sex-specific modulation of the neuroimmune environment.
From a translational perspective, these insights open avenues for new therapeutic strategies targeting microglial CHD8 regulation. Modulating CHD8 activity in adult microglia could recalibrate dysfunctional neuroimmune interactions pervasive in neurodegenerative disorders, depression, and even ASD-like behaviors emerging later in life. Importantly, therapies tailored to consider sex differences in microglial response may enhance precision medicine approaches, mitigating adverse effects and optimizing efficacy.
At the core of this study lies the intricate dance between epigenetics, immune signaling, and neural circuits, orchestrated by a single chromatin remodeler. The evidence suggests CHD8 acts as a pivotal regulator of adult microglial identity and function, balancing pro- and anti-inflammatory signals that underpin neural plasticity and homeostasis. The contextual nature of its activity—shaped by sex hormones, cellular milieu, and age—invites further investigation into dynamic gene-environment interactions shaping brain health.
This research challenges traditional neurocentric models by positioning microglia as active modulators of behavioral and cognitive phenotypes through direct genetic regulation. It bridges molecular neuroscience, immunology, and behavioral science, providing a comprehensive framework to understand how peripheral immune-like cells influence central nervous system function. The compelling sex-dependent effects underscore the necessity of incorporating both male and female subjects in preclinical research to unveil differential disease mechanisms and therapeutic windows.
Advanced RNA sequencing combined with high-resolution imaging techniques in this work generated a rich dataset mapping not only altered gene expression but also spatial and morphological microglial heterogeneity. This multimodal approach allowed the team to correlate transcriptional changes with physical alterations and behavioral outcomes, strengthening causal inferences. The utilization of adult-specific knockdown models represents a methodological leap forward in distinguishing developmental from adult-onset genetic influences on brain function.
These findings resonate deeply within the field of neuropsychiatric disorder research, where CHD8 mutations are among the most penetrant genetic alterations associated with ASD. The adult microglial dimension revealed here expands the potential window for intervention beyond early childhood, highlighting microglia as a therapeutic target in adolescence and adulthood. Moreover, the study enriches the dialogue on sex differences in ASD, depression, and other neuroimmune-linked disorders by unveiling fundamental genetic regulators mediating divergent trajectories.
As the brain’s immune sentinels, microglia serve as mediators between the environment and the neural circuitry. The disruption of CHD8 within these cells underscores how epigenetic regulators govern immune cell reactivity and communication with neurons. Unraveling these pathways may illuminate how systemic inflammation or environmental stressors intersect with genetic vulnerability to precipitate neuropathology. Such integrative perspectives could revolutionize diagnostics and personalized treatment algorithms.
The authors highlight future research directions involving longitudinal studies to track the progression of behavioral and molecular changes following CHD8 modulation. Investigating interactions with sex hormones, aging, and environmental factors will be crucial to dissecting the complexity of microglial plasticity. Additionally, expanding studies to human cells and clinical populations will test translational relevance and guide biomarker development.
In summary, this elite study leverages cutting-edge genetic, imaging, and behavioral approaches to spotlight the indispensable role of CHD8 within adult microglia and its sex-dependent repercussions on brain function. It catapults the field forward, linking chromatin remodeling with neuroimmune regulation and behavioral expression, and forging new paths toward targeted interventions that embrace biological sex as a fundamental axis. The intricate relationship between microglial gene regulation and neurological health unveiled here offers a promising blueprint for the future of neuropsychiatric research and therapy.
Subject of Research: Adult microglial CHD8 knockdown in C57BL6 mice and its sex-dependent effects on behavior, morphology, and transcriptional changes.
Article Title: CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in a sex-dependent manner.
Article References: Weissberg, O., Harari, R., Dogun, C. et al. CHD8 adulthood microglial knockdown in C57BL6 mice induces behavioral, morphological, and transcriptional changes in a sex-dependent manner. Transl Psychiatry 15, 245 (2025). https://doi.org/10.1038/s41398-025-03468-3
DOI: https://doi.org/10.1038/s41398-025-03468-3
Image Credits: AI Generated
