Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder

Abstract

ANK3, encoding the adaptor protein Ankyrin-G, has been implicated in bipolar disorder by genome wide association studies. ANK3 has multiple alternative first exons, and a bipolar disorder-associated ANK3 variant has been shown to reduce expression of exon 1b. Here we identify mechanisms through which reduced ANK3 exon 1b isoform expression disrupts neuronal excitation-inhibition balance. We find that parvalbumin interneurons and principal cells differentially express ANK3 first exon subtypes. Parvalbumin interneurons express only isoforms containing exon 1b, whereas excitatory principal cells express exon 1e alone, or both 1e and 1b. In transgenic mice deficient for exon 1b, parvalbumin interneurons lack voltage-gated sodium channels at their axonal initial segments and have increased firing thresholds and diminished action potential dynamic range. These mice exhibit an Ank3 gene dosage-dependent phenotype including behavior changes modeling bipolar disorder, epilepsy, and sudden death. Thus, ANK3’s important association with human bipolar susceptibility may arise from imbalance between ankyrin-G function in interneurons and principal cells and resultant excessive circuit sensitivity and output. Ankyrin-G isoform imbalance is a novel molecular endophenotype and potential therapeutic target.

Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies

“…Here, ANK3 isoforms containing exon1b are localized to the axon initial segment of PV neurons, and exon1b homozygous knockout mice, as well as PV‐specific ANK3 knock out mice, develop epilepsy. This was due to reduced excitability of PV neurons …”

“…This was due to reduced excitability of PV neurons. 121 A second theory suggests the role for the axons of pyramidal neurons in the prefrontal cortex. This is based on the decrease in ANKG-like immunoreactivity in the axons of pyramidal neurons in the post-mortem prefrontal cortex of schizophrenic patients.…”

“…Bipolar-like symptoms in epileptic patients 40 Epileptic phenotypes of Ank3 mutant mice 121 and Shank3 mutant mice 124…”

Replication, reanalysis, and gene expression: ME2 and genetic generalized epilepsy

“…32 Multiple lines of independent evidence link BD to ME2, suggesting that ME2 may be part of that shared genetic etiology. 32 Multiple lines of independent evidence link BD to ME2, suggesting that ME2 may be part of that shared genetic etiology.…”

“…• ME2 is a gene for genetic generalized epilepsy (GGE) • The genetic association between ME2 and GGE could be mediated by ME2 expression in brain • Our research suggests a possible direct pharmacologic approach to controlling seizures etiology between BD and GGE. 32 Multiple lines of independent evidence link BD to ME2, suggesting that ME2 may be part of that shared genetic etiology. First, several independent studies have identified 18q21 and/or ME2 as a susceptibility locus for BD and/or GGE.…”