title: Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder.
abstract: 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: A Y
authors.initials: AY
authors.lastname: Lopez
authors.affiliation: Department of Zoology and Physiology, University of Wyoming, Laramie, WY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Maheshwari
authors.affiliation: Department of Neurosurgery, Texas Children's Hospital, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Curry
authors.affiliation: Department of Neurosurgery, Texas Children's Hospital, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lam
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston, TX, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Adesina
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Department of Neurology, Baylor College of Medicine, Houston, TX, USA.|Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Noebels
authors.affiliation: Department of Zoology and Physiology, University of Wyoming, Laramie, WY, USA.
authors.forename: Q-Q
authors.initials: QQ
authors.lastname: Sun
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Department of Neurology, Baylor College of Medicine, Houston, TX, USA.|Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Cooper
mesh_terms: D000293:Adolescent; D017398:Alternative Splicing; D000818:Animals; D017487:Ankyrins / Q000235:genetics* / Q000378:metabolism*; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002648:Child; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005091:Exons; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010320:Parvalbumins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms
chemical_list: C490613:ANK3 protein, human; D017487:Ankyrins; D010320:Parvalbumins; D020033:Protein Isoforms