IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex

Cells. 2021 Oct 12;10(10):2724. doi: 10.3390/cells10102724.

Abstract

IQSEC2 is a guanine nucleotide exchange factor (GEF) for ADP-ribosylation factor 6 (Arf6), of which protein is exclusively localized to the postsynaptic density of the excitatory synapse. Human genome studies have revealed that the IQSEC2 gene is associated with X-linked neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism. In this study, we examined the behavior and synapse function in IQSEC2 knockout (KO) mice that we generated using CRIPSR/Cas9-mediated genome editing to solve the relevance between IQSEC2 deficiency and the pathophysiology of neurodevelopmental disorders. IQSEC2 KO mice exhibited autistic behaviors, such as overgrooming and social deficits. We identified that up-regulation of c-Fos expression in the medial prefrontal cortex (mPFC) induced by social stimulation was significantly attenuated in IQSEC2 KO mice. Whole cell electrophysiological recording identified that synaptic transmissions mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), N-methyl-D-aspartate receptor (NMDAR), and γ-aminobutyric acid receptor (GABAR) were significantly decreased in pyramidal neurons in layer 5 of the mPFC in IQSEC2 KO mice. Reexpression of IQSEC2 isoform 1 in the mPFC of IQSEC2 KO mice using adeno-associated virus (AAV) rescued both synaptic and social deficits, suggesting that impaired synaptic function in the mPFC is responsible for social deficits in IQSEC2 KO mice.

Keywords: IQSEC2; autism; medial prefrontal cortex (mPFC); social behavior; synapse.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factor 6
  • Animals
  • Autistic Disorder / pathology*
  • Autistic Disorder / physiopathology*
  • Grooming
  • Guanine Nucleotide Exchange Factors / deficiency*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Net / physiopathology*
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / metabolism
  • Prefrontal Cortex / physiopathology*
  • Protein Isoforms / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism
  • Pyramidal Cells / metabolism
  • Receptors, AMPA / metabolism
  • Receptors, GABA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Social Behavior*
  • Synapses / metabolism
  • Synaptic Transmission
  • Up-Regulation

Substances

  • ADP-Ribosylation Factor 6
  • Guanine Nucleotide Exchange Factors
  • IQSEC2 protein, mouse
  • Nerve Tissue Proteins
  • Protein Isoforms
  • Proto-Oncogene Proteins c-fos
  • Receptors, AMPA
  • Receptors, GABA
  • Receptors, N-Methyl-D-Aspartate
  • ARF6 protein, human
  • Arf6 protein, mouse