Electrophysiological consequences of SCN2A mutations found in autism

  • Awarded: 2015
  • Award Type: Explorer
  • Award #: 362242

The generation of all-or-none action potentials is critical for proper brain function. At the heart of action potential generation are voltage-gated sodium channels, which underlie the rising, or depolarizing, phase of the action potential. Twelve different mutations in the SCN2A gene, which encodes the neuronal sodium channel NaV1.2, have been identified in two large autism genetic studies1,2.

NaV1.2 channels play key roles in both developing and mature excitatory neurons in the brain, including cortical pyramidal cells, whose dysfunction has been implicated in autism. Indeed, SCN2A shows some of the strongest evidence for association with autism of all genes currently identified, but how autism-associated mutations in SCN2A alter the function of the encoded NaV1.2 channel is unknown.

Kevin Bender’s laboratory at the University of California, San Francisco has a longstanding interest in understanding how neurons generate action potentials, and how dysfunctions in action potential generation result in neurological disorders. In this project, Bender and his team will use electrophysiological techniques to determine how autism-associated mutations affect the electrophysiological properties of NaV1.2 channels expressed in cultured cells.

Due to commonalities in the locations of many of these mutations, Bender and his colleagues predict that the majority of the mutations will share a common electrophysiological phenotype. Results from these experiments will be used to inform future studies to determine how these phenotypes alter neuronal function in animal models engineered to harbor these genetic mutations.



1.Iossifov I. et al. Nature 515, 216-221 (2014) PubMed
2.De Rubeis S. et al. Nature 515, 209-215 (2014) PubMed
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