Bipolar disorder and epilepsy linked to turning down an inhibitory switch in brain circuits
Within each ANK3 gene are bits of DNA containing information coding for several different proteins. The research team found that, in both mice and human, different ANK3-coded proteins were expressed on brain cells responsible for increasing output (excitation) and holding back output (inhibition). Working with Cooper, Baylor genetics graduate student Angel Lopez discovered that an ANK3 type found in lower amounts in bipolar disorder patients was selectively lost by inhibitory neurons, lowering their output. Activity of neighboring excitatory cells proved unaffected. So, what scientists call “excitation/inhibition” balance was shifted in the direction of excessive excitation.
When Lopez and colleagues engineered mice to lose this inhibitory form of ANK3, they found that the imbalance caused both frequent epileptic seizures and an increased risk of sudden death across the lifespan.
“This showed us that imbalance in ANK3 function can result not only in excessive circuit sensitivity and output leading to bipolar disorder, but also severe epilepsy,” Cooper said.
Although diagnosis and care for bipolar disorder and epilepsy often are viewed as distinctly psychiatric and neurological issues, respectively, the study highlights an example of common genetic and biological underpinnings at a frontier between medical disciplines. The results open the door to additional lab and clinical research and could lead to new treatment options for both conditions by targeting ANK3 and its molecular partners in the brain.
“Our work also provides an example of how conducting and participating in unbiased human genetic studies, such as those that implicated ANK3 in bipolar disorder, can illuminate unforeseen connections between disease categories and the benefits of research that crosses disciplinary borders” said Cooper.
Others who contributed to the research include Drs. Mingxuan Xu, Atul Maheshwari, David Curry, Sandi Lam, Jeffrey L Noebels, and Adekunle M Adesina, all with Baylor College of Medicine, and Drs. Xinjun Wang and Qian-Quan Sun, at the University of Wyoming in Laramie, WY. Drs. Adesina, Curry and Lam are also faculty at Texas Children’s Hospital.
This study was supported by National Institutes of Health P30 CA125123,
K08 NS096029 (AM), NIH U01 NS090340 (JLN), NIH R01 NS094550 (QQS) and NIH R01NS049119 (ECC).