Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder

A. Y. Lopez, X. Wang, M. Xu, A. Maheshwari, D. Curry, S. Lam, A. M. Adesina, J. L. Noebels, Q. Q. Sun, E. C. Cooper*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

ANK3, encoding the adaptor protein Ankyrin-G (AnkG), has been implicated in bipolar disorder by genome-wide association studies. ANK3 has multiple alternative first exons, and a bipolar disorder-associated ANK3 variant has been shown to reduce the expression of exon 1b. Here we identify mechanisms through which reduced ANK3 exon 1b isoform expression disrupts neuronal excitation–inhibition balance. We find that parvalbumin (PV) interneurons and principal cells differentially express ANK3 first exon subtypes. PV interneurons express only isoforms containing exon 1b, whereas excitatory principal cells express exon 1e alone or both 1e and 1b. In transgenic mice deficient for exon 1b, PV interneurons lack voltage-gated sodium channels at their axonal initial segments and have increased firing thresholds and diminished action potential dynamic range. These mice exhibit an Ank3 gene dosage-dependent phenotype including behavior changes modeling bipolar disorder, epilepsy and sudden death. Thus ANK3’s important association with human bipolar susceptibility may arise from imbalance between AnkG function in interneurons and principal cells and resultant excessive circuit sensitivity and output. AnkG isoform imbalance is a novel molecular endophenotype and potential therapeutic target.

Original languageEnglish (US)
Pages (from-to)1464-1472
Number of pages9
JournalMolecular Psychiatry
Volume22
Issue number10
DOIs
StatePublished - Oct 2017
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder'. Together they form a unique fingerprint.

Cite this