Syngap1regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex

Abstract

AbstractSYNGAP1 haploinsufficiency-related intellectual disability (SYNGAP1-ID) is characterized by moderate to severe ID, generalized epilepsy, autism spectrum disorder, sensory processing dysfunction and other behavioral abnormalities. While numerous studies have highlighted a role of Syngap1 in cortical excitatory neurons development; recent studies suggest that Syngap1 plays a role in GABAergic inhibitory neuron development as well. However, the molecular pathways by which Syngap1 acts on GABAergic neurons, and whether they are similar or different from the mechanisms underlying its effects in excitatory neurons, is unknown. Here, we examined whether, and how, embryonic-onsetSyngap1haploinsufficiency restricted to GABAergic interneurons derived from the medial ganglionic eminence (MGE) impacts their synaptic and intrinsic properties in adult primary auditory cortex (A1). We found thatSyngap1haploinsufficiency affects the intrinsic properties, overall leading to increased firing threshold, and decreased excitatory synaptic drive of Parvalbumin (PV)+ neurons in adult Layer IV A1, whilst Somatostatin (SST)+ interneurons were mostly resistant toSyngap1haploinsufficiency. Further, the AMPA component of thalamocortical evoked-EPSC was decreased in PV+ cells from mutant mice. Finally, we found that the selective blocking of voltage-gated D-type K+ currents was sufficient to rescue PV+ mutant cell-intrinsic properties to wild-type levels. Together, these data suggest thatSyngap1plays a specific role in the maturation of PV+ cell intrinsic properties and synaptic drive, and its haploinsufficiency may lead to reduced PV cell recruitment in the adult A1, which could in turn contribute to the auditory processing alterations found in SYNGAP1-ID preclinical models and patients.