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Ankyrin-G- A novel mechanistic link between epilepsy and bipolar disorder

Angel Y. Lopez3 , Mingxuan Xu1 , Atul Maheshwari1 , Jeffrey L. Noebels1,2,3, Edward C. Cooper1,2,3 1 Department of Neurology Baylor College of Medicine, Houston, Tx 77030-2504, USA 2 Department of Neuroscience Baylor College of Medicine, Houston, Tx 77030-2504, USA 3 Molecular and Human Genetics, Baylor College of Medicine, Houston, Tx 77030-2504, USA The co-morbidity of mood disorders and epilepsy is well-established epidemiologically but poorly understood. Genetics offers a strategy for revealing underlying mechanisms and pathways responsible for this co-morbidity. ANK3 is a gene that has been widely implicated in psychiatric disease. Single nucleotide polymorphisms (SNPs) in ANK3 have shown association with bipolar disorder in multiple, independent genome wide association studies (GWAS). The majority of these SNPs are located in the intronic regions near two alternative first exons of ANK3, exons 1e and 1b. Post mortem human brain tissue studies have shown that individuals containing these SNPs have significantly reduced levels of ANK3 exon 1b transcripts in many brain regions. However, the mechanism(s) by which ANK3 contributes to this disorder is still unknown. ANK3 is a highly conserved, large gene encoding multiple isoforms of a very large (180-480 kDa) protein, Ankyrin-G (AnkG). AnkG isoforms are expressed in almost all tissues and function generally as a molecular linker between integral membrane proteins and the cytoskeleton.

In neurons, AnkG is concentrated at the axon initial segments (AISs) and nodes of Ranvier (NRs) where it binds voltage-gated sodium (NaV) and potassium (Kv) channels necessary for action potential generation and conduction. Consequently, AnkG is essential for the assembly, maintenance, and function of neuronal AISs and NRs. We generated antibodies specifically detecting the two alternative N-terminal peptides encoded by exons 1e and 1b. We found that parvalbumin-positive (PV+) interneurons exclusively express isoforms of AnkG encoded by transcripts that include exon 1b. This pattern was observed in many different brain regions, including limbic system circuits that have roles in mood and emotion. Using quantitative analysis of images obtained by confocal microscopy, we found that heterozygous mice lacking the exon 1b isoforms of ANK3 have significantly reduced AnkG and NaV channel densities at the AIS of PV+ interneurons. Using video EEG monitoring, we observed spontaneous generalized seizures in both heterozygous and homozygous exon 1b-KO mice. The mice also showed marked susceptibility to audiogenic seizures absent in littermate controls.

Thus loss of AnkG from the AISs of PV+ interneurons leads to hyperexcitability in the cortex and epilepsy. We hypothesize that imbalanced inhibition and excitation may underlie the genetic association of ANK3 and mood disorder. Further studies of ANK3 provide an opportunity to examine the nexus between epilepsy and disorders of mood, which is clinically very important and very poorly understood. A role for axonal AnkG-ion channel protein complexes in mood is appealing, given the reciprocal epidemiological association of epilepsy and psychiatric disorders, and the frequent and sometimes efficacious clinical use of NaV channel blockers in both types of disorders.

This work was funded by R01 NS049119-09.