Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function.

Martin H Berryer,Graziella Di Cristo,Nathalie Sanon,Nathalie Lamarche-Vane,Ciprian Bosoi,Paul Xing,Massimo Avoli,Lionel Carmant,Jacques L Michaud,Bidisha Chattopadhyaya,Fadi F Hamdan,Maxime Lévesque,Judith Antoine-Bertrand,Ilse Riebe,Jean-Claude Lacaille

doi:10.1038/ncomms13340

Abstract

Haploinsufficiency of the SYNGAP1 gene, which codes for a Ras GTPase-activating protein, impairs cognition both in humans and in mice. 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 cell-autonomous manner. 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.

Highlights

Haploinsufficiency of the SYNGAP1 gene, which codes for a Ras GTPase-activating protein, impairs cognition both in humans and in mice
To confirm that SYNGAP1 is present in GABAergic neurons, we prepared dissociated neuronal cultures from E18 wild-type embryos and immunostained them for GAD67, which is the main GABA synthesizing enzyme[35], and SYNGAP1 at DIV21, after the peak of synapse formation
We found that GAD67-positive cells co-localized with SYNGAP1 (Supplementary Fig. 1a, 63±5% co-localization), indicating that SYNGAP1 is expressed by GABAergic neurons

Summary

Introduction

Haploinsufficiency of the SYNGAP1 gene, which codes for a Ras GTPase-activating protein, impairs cognition both in humans and in mice. We further show that Syngap[1] 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. Highlighting the importance of GABA interneurons in cognitive functions, cortical circuits in several mouse models of ID and autistic-like behaviour show excitation/inhibition imbalance, which is due to alterations in glutamatergic or GABAergic neurotransmission, or more often, in both[16,22,23,24,25,26,27]. We generated mice with specific deletion of Syngap[1] in GABAergic neurons generated in the medial ganglionic eminence (MGE) to assess its role in the establishment of mature GABAergic connectivity and mouse cognitive function in vivo. We found that Syngap[1] strongly modulated the formation of GABAergic synaptic connectivity and function and that MGE cell-type specific Syngap[1] haploinsufficiency altered cognition

Methods

Results

Conclusion