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A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia

Nature Medicine volume 15, pages 509–518 (2009)Cite this article

Abstract

Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5′ complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go–related K+ channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K+ current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.

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Figure 1: Genetic association of 7q36.1 with risk for schizophrenia.
Figure 2: Association of risk SNPs with cognitive measures, brain structure volumes and regional brain activity during memory-based tasks.
Figure 3: Regional gene expression and association with risk genotype.
Figure 4: Detection and quantification of KCNH2-3.1 mRNA and protein.
Figure 5: Characterization of KCNH2 currents in HEK293T cells expressing KCNH2-1A and KCNH2-3.1.
Figure 6: Effect of KCNH2-3.1 on repolarization-induced tail currents and firing patterns in cortical neurons.

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Acknowledgements

We thank J. Hardy, J. Duckworth and P. Momeni for technical assistance with high G-C content sequencing. We also thank J. Hardy, D. Goldman, A. Law and W. Chen for their very helpful review of the manuscript. We thank R. Straub and M. Mayhew for their input on statistical genetics analysis, M. Barenboim for help with bioinformatics and M. Herman and S. Mitkus for their help with postmortem tissue. We are extremely grateful for the assistance of G. Liu and S. Chen in the cloning and sequencing of KCNH2-3.1. We also would like to thank H.-J. Möller, P. Muglia and coworkers at the Department of Psychiatry, Ludwig Maximilians University for their help with subject recruitment and evaluation. S.J. Huffaker was partially supported by the US National Institutes of Health/Cambridge University Health Science Scholars and Medical Scientist Training Programs. Recruitment of the individuals with schizophrenia at Ludwig Maximilians University was supported by GlaxoSmithKline. Human fetal tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland.

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  1. Andreas Meyer-Lindenberg

    Present address: Current address: Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Germany.,

Authors and Affiliations

  1. Clinical Brain Disorders Branch, National Institute of Mental Health (NIMH), Bethesda, Maryland, USA

    Stephen J Huffaker, Jingshan Chen, Kristin K Nicodemus, Fabio Sambataro, Venkata Mattay, Barbara K Lipska, Thomas M Hyde, Jian Song, Morgan J Proust, Joseph H Callicott, Andreas Meyer-Lindenberg, Michael F Egan, Terry E Goldberg, Joel E Kleinman & Daniel R Weinberger

  2. Genes, Cognition and Psychosis Program, NIMH, Bethesda, Maryland, USA

    Stephen J Huffaker, Jingshan Chen, Kristin K Nicodemus, Fabio Sambataro, Venkata Mattay, Barbara K Lipska, Thomas M Hyde, Jian Song, Andreas Meyer-Lindenberg, Jay Chang, Terry E Goldberg, Joel E Kleinman, Bai Lu & Daniel R Weinberger

  3. Section on Neural Development and Plasticity, National Institute of Child Health and Development, Bethesda, Maryland, USA

    Feng Yang, Jay Chang, Yuanyuan Ji & Bai Lu

  4. Department of Psychiatry, Molecular and Clinical Neurobiology, Ludwig Maximilians University, Munich, Germany

    Dan Rujescu & Ina Giegling

  5. Department of Psychiatry and Medical Psychology, Yerevan State Medical University, Health Ministry of Armenian, Yerevan, Armenia

    Karine Mayilyan & Armen Soghoyan

  6. Department of Neurological and Psychiatric Sciences, Psychiatric Neuroscience Group, Section on Mental Disorders, University of Bari, Bari, Italy

    Grazia Caforio & Alessandro Bertolino

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Contributions

S.J.H. designed the study, collected and analyzed the data and wrote the paper; D.R.W. designed the study, analyzed data and wrote the paper; K.K.N. performed the statistical genetics and wrote the paper; J. Chen, Y.J. and J.S. performed western blot and HEK expression experiments; F.S., V.M., J.H.C., M.J.P. and A.M.-L. performed the imaging experiments and edited the paper; F.Y., B.K.L. and J. Chang performed the electrophysiology experiments; D.R. and I.G. collected the German cohort samples; A.S. and K.M. collected the Armenian cohort samples; A.B. and G.C. collected the Italian data set; B.L., J.E.K. and T.M.H. collected the postmortem cohort samples; D.R.W., J.E.K., M.F.E., T.E.G., T.M.H., V.M. and J.H.C. collected the CBDB cohort samples.

Corresponding author

Correspondence to Daniel R Weinberger.

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Huffaker, S., Chen, J., Nicodemus, K. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat Med 15, 509–518 (2009). https://doi.org/10.1038/nm.1962

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