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

Significance The ANK3 gene locus has been repeatedly shown to confer risk for bipolar disorder in genome-wide association studies. We generated a mouse model with conditional disruption of ANK3 gene in neurons in adult forebrain (Ank-G cKO). The mice showed robust behavioral phenotypes reminiscent of aspects of human mania, ameliorated by antimania drugs. Repeated stress resulted in dramatic behavioral changes between “mania-like” and “depression-like” status, reminiscent of human bipolar disorder. Histological studies imply that cortical microcircuitry alterations are involved in pathogenesis. Overall, we suggest that this Ank-G cKO mouse model recapitulates core features of human bipolar disorder, and may be useful for studying disease pathophysiology and for developing experimental therapeutics. 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.