Ankyrin-G Heterozygous Knockout Mice Display Increased Sensitivity to Social Defeat Stress

The ANK3 locus has been repeatedly found to confer an increased risk for bipolar disorder. ANK3 codes for Ankyrin-G (Ank-G), a scaffold protein concentrated at axon initial segments, nodes of Ranvier, and dendritic spines, where it organizes voltage-gated sodium and potassium channels and cytoskeletal proteins. Mice with homozygous conditional knockout of Ank-G in the adult forebrain display hyperactivity and reduced anxiety-like behaviors, responsive to mood stabilizers. Their behavior switches to a depression-like phenotype when exposed to chronic social defeat stress (SDS), and then spontaneously reverts to baseline hyperactivity. Ank-G heterozygous conditional knockouts (Ank-G Het cKO) have not previously been characterized. Here, we describe the behavior of Ank-G Het cKO mice compared to littermate controls in the open field, elevated plus maze, and forced swim test, under both unstressed and stressed conditions. We found that Ank-G Het cKO is not significantly different from controls at baseline or after chronic SDS. The chronic stress-induced "depression-like" behavioral phenotype is persistent for at least 28 days and is responsive to fluoxetine. Strikingly, Ank-G Het cKO mice display increased sensitivity to a short duration SDS, which does not affect controls. The heterozygous Ank-G genetic model may provide novel insights into the role of Ank-G in the pathophysiology of stress sensitivity and "depression-like" phenotypes and could be useful for studying Ank-G-related gene-environment interactions.