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

Molecular Psychiatry volume 22, pages 1464–1472 (2017)Cite this article

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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.

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References

  1. Krishnan V, Nestler EJ . The molecular neurobiology of depression. Nature 2008; 455: 894–902.

    Article  CAS  Google Scholar 

  2. England MJ, Liverman CT, Schultz AM, Strawbridge LM . Epilepsy across the spectrum: promoting health and understanding. A summary of the Institute of Medicine report. Epilepsy Behav 2012; 25: 266–276.

    Article  Google Scholar 

  3. Craddock N, Sklar P . Genetics of bipolar disorder. Lancet 2013; 381: 1654–1662.

    Article  CAS  Google Scholar 

  4. Mula M, Sander JW . Suicide risk in people with epilepsy taking antiepilepticdrugs. Bipolar Disord 2013; 15: 622–627.

    Article  Google Scholar 

  5. Tondo L, Pompili M, Forte A, Baldessarini RJ . Suicide attempts in bipolar disorders: comprehensive review of 101 reports. Acta Psychiatr Scand 2016; 133: 174–186.

    Article  CAS  Google Scholar 

  6. Hesdorffer DC, Ishihara L, Mynepalli L, Webb DJ, Weil J, Hauser WA . Epilepsy, suicidality, and psychiatric disorders: a bidirectional association. Ann Neurol 2012; 72: 184–191.

    Article  Google Scholar 

  7. Lau C, Ettinger AB, Hamberger S, Fanning K, Reed ML . Do mood instability symptoms in epilepsy represent formal bipolar disorder? Epilepsia 2012; 53: e37–e40.

    Article  Google Scholar 

  8. Garcia-Morales I, de la Pena Mayor P, Kanner AM . Psychiatric comorbidities in epilepsy: identification and treatment. Neurologist 2008; 14: S15–S25.

    Article  Google Scholar 

  9. Wotton CJ, Goldacre MJ . Record-linkage studies of the coexistence of epilepsy and bipolar disorder. Soc Psychiatry Psychiatr Epidemiol 2014; 49: 1483–1488.

    Article  Google Scholar 

  10. Adelow C, Andersson T, Ahlbom A, Tomson T . Hospitalization for psychiatric disorders before and after onset of unprovoked seizures/epilepsy. Neurology 2012; 78: 396–401.

    Article  Google Scholar 

  11. Noebels JL . Single-gene determinants of epilepsy comorbidity. Cold Spring Harb Perspect Med 2015; 5: 1–13.

    Article  CAS  Google Scholar 

  12. Uher R . Gene-environment interactions in severe mental illness. Front Psychiatry 2014; 5: 48.

    Article  Google Scholar 

  13. Ioannidis JP, Thomas G, Daly MJ . Validating, augmenting and refining genome- wide association signals. Nat Rev Genet 2009; 10: 318–329.

    Article  CAS  Google Scholar 

  14. Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, Jones L et al. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 2008; 40: 1056–1058.

    Article  CAS  Google Scholar 

  15. Schulze TG, Detera-Wadleigh SD, Akula N, Gupta A, Kassem L, Steele J et al. Two variants in Ankyrin 3 (ANK3 are independent genetic risk factors for bipolar disorder. Mol Psychiatry 2009; 14: 487–491.

    Article  CAS  Google Scholar 

  16. Scott LJ, Muglia P, Kong XQ, Guan W, Flickinger M, Upmanyu R et al. Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry. Proc Natl Acad Sci USA 2009; 106: 7501–7506.

    Article  CAS  Google Scholar 

  17. Tesli M, Koefoed P, Athanasiu L, Mattingsdal M, Gustafsson O, Agartz I et al. Association analysis of ANK3 gene variants in nordic bipolar disorder and schizophrenia case-control samples. Am J Med Genet B Neuropsychiatr Genet 2011; 156: 969–974.

    Article  CAS  Google Scholar 

  18. Sklar P, Ripke S, Scott LJ, Andreassen OA, Cichon S, Craddock N . Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011; 43: 977–983.

    Article  CAS  Google Scholar 

  19. Muhleisen TW, Leber M, Schulze TG, Strohmaier J, Degenhardt F, Treutlein J et al. Genome-wide association study reveals two new risk loci for bipolar disorder. Nat Commun 2014; 5: 3339.

    Article  Google Scholar 

  20. Zhou D, Lambert S, Malen PL, Carpenter S, Boland LM, Bennett V . AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing. J Cell Biol 1998; 143: 1295–1304.

    Article  CAS  Google Scholar 

  21. Rueckert EH, Barker D, Ruderfer D, Bergen SE, O'Dushlaine C, Luce CJ et al. Cis-acting regulation of brain-specific ANK3 gene expression by a genetic variant associated with bipolar disorder. Mol Psychiatry 2012; 18: 1–8.

    Google Scholar 

  22. Battefeld A, Tran BT, Gavrilis J, Cooper EC, Kole MH . Heteromeric Kv7.2/7.3 channels differentially regulate action potential initiation and conduction in neocortical myelinated axons. J Neurosci 2014; 34: 3719–3732.

    Article  CAS  Google Scholar 

  23. Hu H, Jonas P . A supercritical density of Na+ channels ensures fast signaling in GABAergic interneuron axons. Nat Neurosci 2014; 17: 686–693.

    Article  CAS  Google Scholar 

  24. Schwarz JR, Glassmeier G, Cooper EC, Kao TC, Nodera H, Tabwena D et al. Evidence that KCNQ channels mediate IKs, a slow subthreshold K+ current in the rat node of Ranvier. J Physiol 2006; 573: 1–17.

    Article  Google Scholar 

  25. Xu M, Cooper EC . An ankyrin-G N-terminal gate and protein kinase CK2 dually regulate binding of voltage-gated sodium and KCNQ2/3 potassium channels. J Biol Chem 2015; 290: 16619–16632.

    Article  CAS  Google Scholar 

  26. Noebels J . Pathway-driven discovery of epilepsy genes. Nat Neurosci 2015; 18: 344–350.

    Article  CAS  Google Scholar 

  27. Kay HY, Greene DL, Kang S, Kosenko A, Hoshi N . M-current preservation contributes to anticonvulsant effects of valproic acid. J Clin Invest 2015; 125: 3904–3914.

    Article  Google Scholar 

  28. Geddes JR, Miklowitz DJ . Treatment of bipolar disorder. Lancet 2013; 381: 1672–1682.

    Article  CAS  Google Scholar 

  29. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM et al. The human genome browser at UCSC. Genome Res 2002; 12: 996–1006.

    Article  CAS  Google Scholar 

  30. Quinn EM, Hill M, Anney R, Gill M, Corvin AP, Morris DW . Evidence for cis-acting regulation of ANK3 and CACNA1C gene expression. Bipolar Disord 2010; 12: 440–445.

    Article  CAS  Google Scholar 

  31. Leussis MP, Berry-Scott EM, Saito M, Jhuang H, de Haan G, Alkan O et al. The ANK3 bipolar disorder gene regulates psychiatric-related behaviors that are modulated by lithium and stress. Biol Psychiatry 2013; 73: 683–690.

    Article  CAS  Google Scholar 

  32. Hughes T, Hansson L, Sonderby IE, Athanasiu L, Zuber V, Tesli M et al. A loss-of-function variant in a minor isoform of ANK3 protects against bipolar disorder and schizophrenia. Biol Psychiatry 2016; 80: 323–330.

    Article  CAS  Google Scholar 

  33. Hu H, Gan J, Jonas P . Interneurons. Fast-spiking, parvalbumin(+) GABAergic interneurons: from cellular design to microcircuit function. Science 2014; 345: 1255–1263.

    Article  Google Scholar 

  34. Wilson NR, Runyan CA, Wang FL, Sur M . Division and subtraction by distinct cortical inhibitory networks in vivo. Nature 2012; 488: 343–348.

    Article  CAS  Google Scholar 

  35. Atallah BV, Bruns W, Carandini M, Scanziani M . Parvalbumin-expressing interneurons linearly transform cortical responses to visual stimuli. Neuron 2012; 73: 159–170.

    Article  CAS  Google Scholar 

  36. Jenkins PM, Vasavda C, Hostettler J, Davis JQ, Abdi K, Bennett V. . E-cadherin polarity is determined by a multifunction motif mediating lateral membrane retention through ankyrin-G and apical-lateral transcytosis through clathrin. J Biol Chem 2013; 288: 14018–14031.

    Article  CAS  Google Scholar 

  37. Maheshwari A, Nahm WK, Noebels JL . Paradoxical proepileptic response to NMDA receptor blockade linked to cortical interneuron defect in stargazer mice. Front Cell Neurosci 2013; 7: 156.

    Article  Google Scholar 

  38. Pan Z, Kao T, Horvath Z, Lemos J, Sul JY, Cranstoun SD et al. A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J Neurosci 2006; 26: 2599–2613.

    Article  CAS  Google Scholar 

  39. Paxinos G, Franklin K . The Mouse Brain in Stereotaxic Coordinates. Academic Press: San Diego, California, USA, 1997.

    Google Scholar 

  40. Agmon A, Connors BW . Thalamocortical responses of mouse somatosensory (barrel) cortex in vitro. Neuroscience 1995; 41: 365–379.

    Article  Google Scholar 

  41. Agmon A, Yang LT, Jones EG, O'Dowd DK . Topological precision in the thalamic projection to neonatal mouse barrel cortex. J Neurosci 1995; 15: 549–561.

    Article  CAS  Google Scholar 

  42. Zhang Z, Sun QQ . Development of NMDA NR2 subunits and their roles in critical period maturation of neocortical GABAergic interneurons. Dev Neurobiol 2011; 71: 221–245.

    Article  CAS  Google Scholar 

  43. Kordeli E, Lambert S, Bennett V . AnkyrinG. A new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier. J Biol Chem 1995; 270: 2352–2359.

    Article  CAS  Google Scholar 

  44. Townsend J, Altshuler LL . Emotion processing and regulation in bipolar disorder: a review. Bipolar Disord 2012; 14: 326–339.

    Article  Google Scholar 

  45. Zhang ZJ, Reynolds GP . A selective decrease in the relative density of parvalbumin-immunoreactive neurons in the hippocampus in schizophrenia. Schizophr Res 2002; 55: 1–10.

    Article  Google Scholar 

  46. Marin O . Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci 2012; 13: 107–120.

    Article  CAS  Google Scholar 

  47. Maheshwari A, Noebels JL . Monogenic models of absence epilepsy: windows into the complex balance between inhibition and excitation in thalamocortical microcircuits. Prog Brain Res 2014; 213: 223–252.

    Article  Google Scholar 

  48. Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 2010; 468: 263–269.

    Article  CAS  Google Scholar 

  49. Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I et al. NaV1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J Neurosci 2007; 27: 5903–5914.

    Article  CAS  Google Scholar 

  50. Borg-Graham LJ, Monier C, Fregnac Y . Visual input evokes transient and strong shunting inhibition in visual cortical neurons. Nature 1998; 393: 369–373.

    Article  CAS  Google Scholar 

  51. Zhang Z, Jiao YY, Sun QQ . Developmental maturation of excitation and inhibition balance in principal neurons across four layers of somatosensory cortex. Neuroscience 2011; 174: 10–25.

    Article  CAS  Google Scholar 

  52. Cruikshank SJ, Lewis TJ, Connors BW . Synaptic basis for intense thalamocortical activation of feedforward inhibitory cells in neocortex. Nat Neurosci 2007; 10: 462–468.

    Article  CAS  Google Scholar 

  53. Sun QQ, Huguenard JR, Prince DA . Barrel cortex microcircuits: thalamocortical feedforward inhibition in spiny stellate cells is mediated by a small number of fast-spiking interneurons. J Neurosci 2006; 26: 1219–1230.

    Article  CAS  Google Scholar 

  54. Iqbal Z, Vandeweyer G, van der Voet M, Waryah AM, Zahoor MY, Besseling JA et al. Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. Hum Mol Genet 2013; 22: 1960–1970.

    Article  CAS  Google Scholar 

  55. Doyle GA, Lai AT, Chou AD, Wang MJ, Gai X, Rappaport EF et al. Re-sequencing of ankyrin 3 exon 48 and case-control association analysis of rare variants in bipolar disorder type I. Bipolar Disord 2012; 14: 809–821.

    Article  CAS  Google Scholar 

  56. Poduri A . Meta-analysis revives genome-wide association studies in epilepsy. Epilepsy Curr 2015; 15: 122–123.

    Article  Google Scholar 

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Acknowledgements

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).

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    A Y Lopez, J L Noebels & E C Cooper

  2. Department of Zoology and Physiology, University of Wyoming, Laramie, WY, USA

    X Wang & Q-Q Sun

  3. Department of Neurology, Baylor College of Medicine, Houston, TX, USA

    M Xu, A Maheshwari, J L Noebels & E C Cooper

  4. Department of Neurosurgery, Texas Children’s Hospital, Houston, TX, USA

    D Curry & S Lam

  5. Department of Pathology, Texas Children’s Hospital, Houston, TX, USA

    A M Adesina

  6. Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA

    J L Noebels & E C Cooper

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Correspondence to E C Cooper.

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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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