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- Title
A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia.
- Authors
Huffaker, Stephen J; Chen, Jingshan; Nicodemus, Kristin K; Sambataro, Fabio; Yang, Feng; Mattay, Venkata; Lipska, Barbara K; Hyde, Thomas M; Song, Jian; Rujescu, Dan; Giegling, Ina; Mayilyan, Karine; Proust, Morgan J; Soghoyan, Armen; Caforio, Grazia; Callicott, Joseph H; Bertolino, Alessandro; Meyer-Lindenberg, Andreas; Chang, Jay; Ji, Yuanyuan; Egan, Michael F; Goldberg, Terry E; Kleinman, Joel E; Lu, Bai; Weinberger, Daniel R
- 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.
- Publication
Nature medicine, 2009, Vol 15, Issue 5, p509
- ISSN
1546-170X
- Publication type
Journal Article
- DOI
10.1038/nm.1962