Epigenetic Modulation to perturb the SYNGAP1 Intellectual Disability (ID) that ameliorates synaptic and behavioural deficits

Singh, A. K.; Joshi, I.; Reddy, N. M. N.; Purushotham, S. S.; Eswaramoorth, M.; Vasudevan, M.; Banerjee, S.; Clement, J. P.; Kundu, T. K.

doi:10.1101/2024.01.03.574003

bioRxiv · 10.1101/2024.01.03.574003

Epigenetic Modulation to perturb the SYNGAP1 Intellectual Disability (ID) that ameliorates synaptic and behavioural deficits

Singh, A. K.·Joshi, I.·Reddy, N. M. N.·Purushotham, S. S.·Eswaramoorth, M.·Vasudevan, M.·Banerjee, S.·Clement, J. P.·Kundu, T. K.

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Abstract

Sporadic heterozygous mutations in SYNGAP1 affects 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 of SYNGAP1 mutation-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 of Syngap1+/- mouse. To establish the causal relationship of Syngap1+/- phenotype and the altered histone acetylation signature we have treated 2-4 months old Syngap1+/- 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 of Syngap1+/- 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).

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Singh, A. K., Joshi, I., Reddy, N. M. N., Purushotham, S. S., Eswaramoorth, M., Vasudevan, M., Banerjee, S., Clement, J. P., Kundu, T. K.. 2024-01-03. Epigenetic Modulation to perturb the SYNGAP1 Intellectual Disability (ID) that ameliorates synaptic and behavioural deficits. https://doi.org/10.1101/2024.01.03.574003

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