
Syngap1 haploinsufficiency in medial ganglionic eminence-derived interneurons, particularly parvalbumin-positive cells, leads to reduced synaptic excitation, decreased intrinsic excitability, and altered dendritic development, which may underlie auditory processing deficits in SYNGAP1-related intellectual disability.


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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 most studies, so far, have focussed on the role of Syngap1 in cortical excitatory neurons, 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-onset Syngap1 haploinsufficiency restricted to GABAergic interneurons derived from the medial ganglionic eminence (MGE) impacts their synaptic and intrinsic properties in adulthood. We found that Syngap1 haploinsufficiency affects the intrinsic properties, overall leading to increased firing threshold, and decreased excitatory synaptic drive of Parvalbumin (PV)+ neurons from Layer IV auditory cortex in adult mice, whilst Somatostatin (SST)+ interneurons were mostly resistant to Syngap1 haploinsufficiency. Further, the AMPA component of thalamocortical evoked-EPSC was decreased in PV+ cells from mutant mice. Finally, we found that targeting the Kv1 family of voltage-gated potassium channels 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 auditory cortex, which could thus underlie the auditory processing alterations found in SYNGAP1-ID preclinical models and patients.

### Competing Interest Statement

The authors have declared no competing interest.

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

syngap1-haploinsufficiency-impairs-synaptic-drive-and-intrinsic-excitability-of-parvalbumin-positive-interneurons-in-mouse-auditory-cortex


Syngap1 Haploinsufficiency Impairs Synaptic Drive and Intrinsic Excitability of Parvalbumin-Positive Interneurons in Mouse Auditory Cortex
