Syngap1 regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex

Abstract

SYNGAP1 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, are unknown. Here, we examined whether, and how, embryonic-onset Syngap1 haploinsufficiency 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 that Syngap1 haploinsufficiency significantly affected the intrinsic properties, overall leading to increased firing threshold and decreased excitatory synaptic drive in Parvalbumin (PV)+ neurons in adult layer IV A1. Further, the AMPA component of thalamocortical evoked EPSC was decreased in PV+ cells from mutant mice. Mutant somatostatin (SST)+ interneurons exhibited decreased spontaneous excitatory input and impaired evoked firing without alterations in firing threshold. 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 that Syngap1 plays 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.

Keywords

• intrinsic properties
• cortical GABAergic interneurons
• glutamatergic synapses
• auditory cortex
• Syngap1