Article abstract
Nature Medicine 15, 509 - 518 (2009)
Published online: 3 May 2009 | doi:10.1038/nm.1962
A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia
Stephen J Huffaker1,2, Jingshan Chen1,2, Kristin K Nicodemus1,2, Fabio Sambataro1,2, Feng Yang3, Venkata Mattay1,2, Barbara K Lipska1,2, Thomas M Hyde1,2, Jian Song1,2, Dan Rujescu4, Ina Giegling4, Karine Mayilyan5, Morgan J Proust1, Armen Soghoyan5, Grazia Caforio6, Joseph H Callicott1, Alessandro Bertolino6, Andreas Meyer-Lindenberg1,2,7, Jay Chang2,3, Yuanyuan Ji3, Michael F Egan1, Terry E Goldberg1,2, Joel E Kleinman1,2, Bai Lu2,3 & Daniel R Weinberger1,2
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.
- Clinical Brain Disorders Branch, National Institute of Mental Health (NIMH), Bethesda, Maryland, USA.
- Genes, Cognition and Psychosis Program, NIMH, Bethesda, Maryland, USA.
- Section on Neural Development and Plasticity, National Institute of Child Health and Development, Bethesda, Maryland, USA.
- Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig Maximilians University, Munich, Germany.
- Department of Psychiatry and Medical Psychology, Yerevan State Medical University, Health Ministry of Armenian, Yerevan, Armenia.
- Psychiatric Neuroscience Group, Section on Mental Disorders, Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy.
- Current address: Central Institute of Mental Health, University of Heidelberg/Medical Faculty Mannheim, Germany.
Correspondence to: Daniel R Weinberger1,2 e-mail: weinberd@mail.nih.gov
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