Methodological frameworks to probe histone acetylation-driven circuit plasticity in SYNGAP1-associated...

SYNGAP1 encodes a Ras GTPase-activating protein essential for neurodevelopment and synaptic plasticity, and heterozygous loss-of-function mutations are strongly associated with intellectual disability (ID) and autism spectrum disorder (ASD). While synaptic and circuit-level impairments resulting from SYNGAP1 haploinsufficiency have been well characterized, the contribution of epigenetic dysregulation remains poorly understood. In this chapter, we describe experimental approaches to investigate histone acetylation-dependent mechanisms underlying SYNGAP1-associated neurodevelopmental phenotypes. Using Syngap1^+/- mice, we demonstrate a robust reduction in p300/CBP-specific histone acetylation marks in the adolescent hippocampus, accompanied by impaired dendritic arborization of adult-born doublecortin-positive (DCX⁺) neurons, indicative of disrupted adult hippocampal neurogenesis. To establish causality between altered chromatin state and behavioural and circuit dysfunction, we employed a glucose-derived carbon nanosphere-conjugated small-molecule activator of p300/CBP (CSP-TTK21) in young adult Syngap1^+/- mice (2-4 months). Pharmacological enhancement of p300/CBP activity restored histone acetylation, rescued synaptic and structural plasticity, normalized experience-dependent cortical circuit reorganization, and significantly improved behavioural performance to levels comparable with wild-type littermates. Transcriptomic profiling by hippocampal RNA sequencing revealed reversal of dysregulated gene expression programs, including key regulators of synaptic plasticity and neurogenesis. Collectively, the methods described in this chapter provide a framework for dissecting epigenetic contributions to SYNGAP1-associated neurodevelopmental disorders and establish chromatin-targeted modulation of p300/CBP as a reversible and therapeutically actionable mechanism for ID/ASD-related circuit dysfunction.