ANK3, encoding the adaptor protein Ankyrin-G (AnkG), 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 the 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 (PV) interneurons and principal cells differentially express ANK3 first exon subtypes. PV 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, PV 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 AnkG function in interneurons and principal cells and resultant excessive circuit sensitivity and output. AnkG isoform imbalance is a novel molecular endophenotype and potential therapeutic target.
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We thank Mia Cooper for excellent technical assistance; Vann Bennett for generous gifts of AnkG antibodies, cDNA and transgenic mouse lines; and the Baylor College of Medicine Genetically Engineered Mouse Core for rederivation of transgenic mice. We also acknowledge Maarten Kole for helpful comments on an earlier version of the manuscript, and members of the Cooper laboratory, Matthew Rasband and Rodney Samaco for helpful discussions. This study was supported by NIH P30 CA125123, NIH K08 NS096029 (AM), NIH U01 NS090340 (JLN), NIH R01 NS094550 (QQS) and NIH R01 NS049119 (ECC).
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Lopez, A., Wang, X., Xu, M. et al. Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder. Mol Psychiatry 22, 1464–1472 (2017). https://doi.org/10.1038/mp.2016.233
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