Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes

Katsanevaki, D.; Till, S. M.; Buller-Peralta, I.; Watson, T. C.; Nawaz, M. S.; Arkell, D.; Tiwari, S.; Kapgal, V.; Biswal, S.; Smith, J. A.; Anstey, N. J.; Mizen, L.; Perentos, N.; Jones, M. W.; Cousin, M. A.; Chattarji, S.; Gonzalez-Sulser, A.; Hardt, O.; Wood, E. R.; Kind, P. C.

doi:10.1101/2020.10.14.339192

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bioRxiv · 10.1101/2020.10.14.339192

Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes

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Abstract

Pathogenic variants in SYNGAP1 are one of the most common genetic causes of nonsyndromic intellectual disability (ID) and are considered a risk for autism spectrum disorder (ASD). SYNGAP1 encodes a synaptic GTPase activating protein that modulates the intrinsic GTPase activity of several small G-proteins and is implicated in regulating the composition of the postsynaptic density. By targeting the deletion of exons encoding the calcium/lipid binding (C2) and GTPase activating protein (GAP) domains, we generated a novel rat model to study SYNGAP related pathophysiology. We find that rats heterozygous for the C2/GAP domain deletion (Syngap+/{Delta}-GAP) exhibit reduced exploration and fear extinction, altered social behaviour, and spontaneous seizures, while homozygous mutants die within days after birth. This new rat model reveals that the enzymatic domains of SYNGAP are essential for normal brain function and provide an important new model system in the study of both ID/ASD and epilepsy.

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Katsanevaki, D., Till, S. M., Buller-Peralta, I., Watson, T. C., Nawaz, M. S., Arkell, D., Tiwari, S., Kapgal, V., Biswal, S., Smith, J. A., Anstey, N. J., Mizen, L., Perentos, N., Jones, M. W., Cousin, M. A., Chattarji, S., Gonzalez-Sulser, A., Hardt, O., Wood, E. R., Kind, P. C.. 2020-10-14. Heterozygous deletion of SYNGAP enzymatic domains in rats causes selective learning, social and seizure phenotypes. https://doi.org/10.1101/2020.10.14.339192

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