Function of the Ankyrin3 Bipolar Disorder Risk Gene in Brain and Behavior

Genome-wide association studies of bipolar disorder (BD) have highlighted a number of genes associated with BD. Among them, ankyrin 3 (ANK3) has been repeatedly and reliably identified. However, the role of ankyrin 3 in the pathophysiology of BD is largely unknown. ANK3 encodes the ankyrin G protein and functions in scaffolding integral membrane proteins to the cytoskeleton. This study, together with previous work from our lab, indicates that disruption of the brain-specific isoform of ankyrin 3 (Ank3+/-) leads to impulsive-like behaviors in mice that are prominent features of BD. Also our work indicates these mice exhibit increased sensitivity to stress, which is a risk factor of BD. Furthermore, neuronal activity in the dentate gyrus within the hippocampus of Ank3 +/- mice is significantly blunted, suggesting an impairment in overall hippocampal function. Treatment of the Ank3 +/- mice with the mood stabilizer lithium rescues the impulsive-like phenotype and restores the neuronal activity in the dentate gyrus. These data provide a biological link between the impulsive-like phenotype and impaired neuronal activity in the Ank3+/- mice. Molecular profiling of the hippocampus suggests that reduced ankyrin G leads to microtubule instability, thus reducing axonal guidance and nuclear localization of key transcription factors. Altogether, these findings reveal cellular and molecular mechanisms underlying the impulsive-like phenotype associated with brain-specific Ank3 disruption and will ultimately lead to a better understanding of the pathophysiology of psychiatric illnesses such as BD