Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder

Shanshan Zhu, Zachary A. Cordner, Jiali Xiong, Chi Tso Chiu, Arabiye Artola, Yanning Zuo, Andrew D. Nelson, Tae Yeon Kim, Natalya Zaika, Brian M. Woolums, Evan J. Hess, Xiaofang Wang, De Maw Chuang, Mikhail M. Pletnikov, Paul M. Jenkins, Kellie L. Tamashiro, Christopher A. Ross

Research output: Contribution to journalArticlepeer-review

Abstract

Genome-wide association studies have implicated the ANK3 locus in bipolar disorder, a major human psychotic illness. ANK3 encodes ankyrin-G, which organizes the neuronal axon initial segment (AIS). We generated a mouse model with conditional disruption of ANK3 in pyramidal neurons of the adult forebrain (Ank-G cKO). This resulted in the expected loss of pyramidal neuron AIS voltage-gated sodium and potassium channels. There was also dramatic loss of markers of afferent GABAergic cartridge synapses, resembling the cortical microcircuitry changes in brains from psychotic patients, and suggesting disinhibition. Expression of c-fos was increased in cortical pyramidal neurons, consistent with increased neuronal activity due to disinhibition. The mice showed robust behavioral phenotypes reminiscent of aspects of human mania, ameliorated by antimania drugs lithium and valproate. Repeated social defeat stress resulted in repeated episodes of dramatic behavioral changes from hyperactivity to “depression-like” behavior, suggestive of some aspects of human bipolar disorder. Overall, we suggest that this Ank-G cKO mouse model recapitulates some of the core features of human bipolar disorder and indicates that cortical microcircuitry alterations during adulthood may be involved in pathogenesis. The model may be useful for studying disease pathophysiology and for developing experimental therapeutics.

Original languageEnglish (US)
Pages (from-to)10479-10484
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number39
DOIs
StatePublished - Sep 26 2017

Keywords

  • ANK3
  • Axon initial segment
  • Chandelier synapse
  • Lithium
  • Mania

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Genetic disruption of ankyrin-G in adult mouse forebrain causes cortical synapse alteration and behavior reminiscent of bipolar disorder'. Together they form a unique fingerprint.

Cite this