Selective dysregulation of hippocampal inhibition in the mouse lacking autism candidate gene CNTNAP2

Sofia Jurgensen, Pablo E. Castillo

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Mutations in the human gene encoding contactin-associated protein-like 2 (CNTNAP2) have been strongly associated with autism spectrum disorders (ASDs). Cntnap2_/_ mice recapitulate major features of ASD, including social impairment, reduced vocalizations, and repetitive behavior. In addition, Cntnap2_/_ mice show reduced cortical neuronal synchrony and develop spontaneous seizures throughout adulthood. As suggested for other forms of ASDs, this phenotype could reflect some form of synaptic dysregulation. However, the impact of lifelong deletion of CNTNAP2 on synaptic function in the brain remains unknown. To address this issue, we have assessed excitatory and inhibitory synaptic transmission in acute hippocampal slices of Cntnap2_/_ mice. We found that although excitatory transmission was mostly normal, inhibition onto CA1 pyramidal cells was altered in Cntnap2_/_mice. Specifically, putative perisomatic, but not dendritic, evoked IPSCs were significantly reduced in these mice. Whereas both inhibitory short-term plasticity and miniature IPSC frequency and amplitude were normal in Cntnap2_/_ mice, we found an unexpected increase in the frequency of spontaneous, action potential-driven IPSCs. Altered hippocampal inhibition could account for the behavioral phenotype Cntnap2_/_ mice present later in life. Overall, our findings that Cntnap2 deletion selectively impairs perisomatic hippocampal inhibition while sparing excitation provide additional support for synaptic dysfunction as a common mechanism underlying ASDs.

Original languageEnglish (US)
Pages (from-to)14681-14687
Number of pages7
JournalJournal of Neuroscience
Volume35
Issue number43
DOIs
StatePublished - Oct 28 2015

Keywords

  • CASPR2
  • Cell adhesion
  • E/I balance
  • Epilepsy
  • Perisomatic inhibition
  • Synaptopathy

ASJC Scopus subject areas

  • Neuroscience(all)

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