Epigenetic Modulation to perturb theSYNGAP1Intellectual Disability (ID) that ameliorates synaptic and behavioural deficits

Abstract

Sporadic heterozygous mutations inSYNGAP1affects social and emotional behaviour that are often observed in intellectual disability (ID) and autism spectrum disorder (ASD). Although neurophysiological deficits have been extensively studied, the epigenetic landscape ofSYNGAP1mutation-mediated intellectual disability is unexplored. Here, we have surprisingly found that the p300/CBP specific acetylation marks of histones are significantly repressed in the adolescent hippocampus ofSyngap1+/-mouse. To establish the causal relationship ofSyngap1+/-phenotype and the altered histone acetylation signature we have treated 2-4 months oldSyngap1+/-mouse with glucose-derived carbon nanosphere (CSP) conjugated potent small molecule activator (TTK21) of p300/CBP lysine acetyltransferase (CSP-TTK21). The enhancement of the p300/CBP specific acetylation marks of histones by CSP-TTK21 restored deficits in spine density, synaptic function, and social preferences ofSyngap1+/-mouse that is very closely comparable to wild type littermates. The hippocampal RNA-Seq analysis of the treated mice revealed that the expression of many critical genes related to the ID/ASD reversed due to the treatment of the specific small molecule activator. This study could be the first demonstration of the reversal of autistic behaviour and neural wiring upon the modulation of altered epigenetic modification (s).