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Proc Natl Acad Sci U S A. 2017 Sep 26;114(39):10479-10484. doi: 10.1073/pnas.1700689114. Epub 2017 Sep 11.

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

Author information

1
Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine (JHU SOM), Baltimore, MD 21287.
2
Department of Psychiatry, JHU SOM, Baltimore, MD 21287.
3
Section on Molecular Neurobiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892.
4
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109.
5
Department of Pharmacology and Molecular Sciences, JHU SOM, Baltimore, MD 21287.
6
The Solomon H. Snyder Department of Neuroscience, JHU SOM, Baltimore, MD 21287.
7
Department of Molecular and Comparative Pathobiology, JHU SOM, Baltimore, MD 21287.
8
W. Harry Feinstone Department of Molecular Microbiology and Immunology, JHU Bloomberg School of Public Health, Baltimore, MD 21287.
9
Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI 48109.
10
Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine (JHU SOM), Baltimore, MD 21287; caross@jhu.edu.
11
Department of Neurology, JHU SOM, Baltimore, MD 21287.

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.

KEYWORDS:

ANK3; axon initial segment; chandelier synapse; lithium; mania

PMID:
28894008
PMCID:
PMC5625892
DOI:
10.1073/pnas.1700689114
[Indexed for MEDLINE]
Free PMC Article

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