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.