Wednesday, April 2, 2025
4/2/2025
Chd8-dependent molecular and functional vulnerabilities in developed cerebellar limbic circuits - The varied and complex symptoms of neurodevelopmental disorders (NDDs) present significant challenges for the development of effective treatments. To provide targeted interventions, an understanding of neurobiological etiology is imperative. Studies have uncovered strong single gene risk factors for NDDs, prominent among which are genes coding for chromatin remodelers. The chromatin remodeler CHD8 has emerged among such genes with one of the highest frequency of de novo mutations in ASD cohorts. Intriguingly, CHD8 mutations have also been discovered in other neurological disorder cohorts, including schizophrenia and obsessive compulsive disorder (OCD). Thus, CHD8 represents a model for rare monogenic NDDs, with a common core set of symptoms associated with ASD, but overall broad and complex expressivity spanning early development through adulthood. Various Chd8 mouse models have been generated, with constitutive mutants exhibiting NDD-relevant phenotypes. However, in these models the wide expression of Chd8 and its involvement in early development have hampered dissociation of developmental effects from effects on mature neurons. Moreover, experimental emphasis on the cerebral cortex and hippocampus has limited advancement from genetic findings to causal neurobiology. The cerebellum (CB) has been consistently and causally associated with NDDs, including in emerging studies of developmental roles of Chd8, and has been implicated in schizophrenia and OCD. Even though roles of the CB have expanded from a motor control center to include cognitive and affective (i.e., limbic) functionality, CB non-motor contributions and pathology remain understudied in neuropsychiatric and NDD research compared to forebrain regions. Further, CB studies in NDDs have primarily investigated developmental impacts. However, Chd8 expression persists in the adult CB. This raises the novel hypothesis that conditional Chd8 deletion in the adult CB contributes to neuropsychiatric and NDD-relevant pathology. Here we propose initial work toward testing this model, defining the impact of conditional Chd8 ablation on adult CB function across behavioral, genomic and electrophysiological dimensions. In two aims, we will manipulate Chd8 expression in CB output nuclei and test CB-specific vulnerabilities in limbic behaviors; investigate CB transcriptomic phenotypes; and begin to probe pathology in the functional connectivity of CB output circuits to the limbic system. These experiments will establish impacts of conditional Chd8 ablation on the developed CB and output circuits; pinpoint molecular underpinnings of CB dysfunction; and begin to build a circuit-level understanding of how Chd8 ablation impacts CB connectivity with the rest of the brain. If successful, this work will lead to new avenues of research on CB dysfunction in NDDs by linking a high confidence risk gene with behavioral, cellular, molecular, and circuit deficits in the CB. By pinpointing biological processes and circuits that remain vulnerable to Chd8 ablation in the developed CB, this line of research has the potential to identify novel therapeutic targets over a time-extended treatment window.
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