Molecular and cellular basis of a neuro-developmental disorder caused by SYNGAP1 haploinsufficiency

Haploinsufficiency of the SYNGAP1 gene, which codes for a Ras GTPase activating protein, impairs cognition both in humans and in mice. Its haploinsufficiency results in an increased level of Ras activity and ERK phosphorylation, abnormal dendritic spine morphogenesis, and an excess of postsynaptic AMPA receptors in excitatory neurons. Specifically, it has been suggested that prematurely increased insertion of AMPA receptors into excitatory synapses could explain some of the phenotypes observed in Syngap1+/- mice. Conversely, the role of Syngap1 haploinsufficiency in GABAergic circuits is unknown. The aims of my thesis project were: 1), to identify the impact of human mutations on SYNGAP1 function; 2) to determine whether SYNGAP1 plays a role in GABAergic circuit development and function, and 3) to reveal how Syngap1 haploinsufficiency specifically in GABAergic circuits affects cognitive behavior. We reported the first de novo missense mutations as well as two de novo novel truncating mutations in SYNGAP1 in humans. These mutations are de novo, except c.283dupC, which was inherited from a mosaic parent. In this study, we confirmed that patients with these mutations in SYNGAP1 showed, among other phenotypes, behavioral disorders associated with intellectual deficiency. Biolistic transfection suggests that these mutations in SYNGAP1 result in a loss of function, most probably disrupting brain development via a mechanism of haploinsufficiency. Decrease of Syngap1 in mice has been previously shown to cause cognitive deficits at least in part by inducing alterations in glutamatergic neurotransmission and premature maturation of excitatory connections. Whether Syngap1 plays a role in the development of cortical GABAergic connectivity and function remains unclear. Here, we show that Syngap1 haploinsufficiency significantly reduces the formation of perisomatic innervations by parvalbumin-positive basket cells, a major population of GABAergic neurons, in a cellautonomous fashion. We further show that Syngap1 haploinsufficiency in GABAergic cells derived from the medial ganglionic eminence impairs their connectivity, reduces inhibitory synaptic activity and cortical gamma oscillation power and causes cognitive deficits. Our results indicate that Syngap1 plays a critical role in GABAergic circuit function and further suggest that Syngap1 haploinsufficiency in GABAergic circuits may contribute to cognitive deficits. All together, my PhD work first, demonstrated that human mutations in the SYNGAP1 gene associated with intellectual deficiency likely cause Syngap1 haploinsufficiency, and second, revealed for the first time a significant role of SYNGAP1 in the regulation of the development and function of GABAergic interneurons.