Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function.
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.
Department of Neurosciences, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Quebec, Canada H3C 3J7.|CHU Sainte-Justine Research Center, 3175 Côte-ste-Catherine, Montréal, Quebec, Canada H3T 1C5.
Martin H
MH
Berryer
Department of Neurosciences, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Quebec, Canada H3C 3J7.|CHU Sainte-Justine Research Center, 3175 Côte-ste-Catherine, Montréal, Quebec, Canada H3T 1C5.
Bidisha
B
Chattopadhyaya
Department of Neurosciences, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Quebec, Canada H3C 3J7.|CHU Sainte-Justine Research Center, 3175 Côte-ste-Catherine, Montréal, Quebec, Canada H3T 1C5.
Paul
P
Xing
Department of Neurosciences, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Quebec, Canada H3C 3J7.|Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, Quebec, Canada H3C 3J7.
Ilse
I
Riebe
CHU Sainte-Justine Research Center, 3175 Côte-ste-Catherine, Montréal, Quebec, Canada H3T 1C5.
Ciprian
C
Bosoi
CHU Sainte-Justine Research Center, 3175 Côte-ste-Catherine, Montréal, Quebec, Canada H3T 1C5.
Nathalie
N
Sanon
Department of Anatomy and Cell Biology, Cancer Research Program of the Research Institute of MUHC, McGill University, 2155 Guy Street, Suite 500, Montreal, Quebec, Canada H3H 2R9.
Judith
J
Antoine-Bertrand
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4.
Maxime
M
Lévesque
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4.
Massimo
M
Avoli
CHU Sainte-Justine Research Center, 3175 Côte-ste-Catherine, Montréal, Quebec, Canada H3T 1C5.
Fadi F
FF
Hamdan
Department of Neurosciences, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Quebec, Canada H3C 3J7.|CHU Sainte-Justine Research Center, 3175 Côte-ste-Catherine, Montréal, Quebec, Canada H3T 1C5.
Lionel
L
Carmant
Department of Anatomy and Cell Biology, Cancer Research Program of the Research Institute of MUHC, McGill University, 2155 Guy Street, Suite 500, Montreal, Quebec, Canada H3H 2R9.
Nathalie
N
Lamarche-Vane
Department of Neurosciences, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Quebec, Canada H3C 3J7.|Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, Quebec, Canada H3C 3J7.
Jean-Claude
0000-0003-4056-0574
JC
Lacaille
Department of Neurosciences, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Quebec, Canada H3C 3J7.|CHU Sainte-Justine Research Center, 3175 Côte-ste-Catherine, Montréal, Quebec, Canada H3T 1C5.|Department of Pediatrics, Université de Montréal, CHU Sainte-Justine, 3175, chemin de la Côte-Sainte-Catherine, 7th floor, block 9, Montreal, Quebec, Canada H3T 1C5.
Jacques L
JL
Michaud
Department of Neurosciences, Université de Montréal, C.P. 6128, Succ. Centre-Ville, Montréal, Quebec, Canada H3C 3J7.|CHU Sainte-Justine Research Center, 3175 Côte-ste-Catherine, Montréal, Quebec, Canada H3T 1C5.
Graziella
G
Di Cristo
D000818:Animals; D002478:Cells, Cultured; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D059330:GABAergic Neurons / Q000502:physiology*; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000502:physiology*
C484512:Syngap1 protein, mouse; D020703:ras GTPase-Activating Proteins