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

Stephen J Huffaker, Jingshan Chen, Kristin K Nicodemus, Fabio Sambataro, Feng Yang, Venkata S Mattay, Barbara K. Lipska, Thomas M Hyde, Jian Song, Dan Rujescu, Ina Giegling, Karine Mayilyan, Morgan J Proust, Armen Soghoyan, Grazia Caforio, Joseph H Callicott, Alessandro Bertolino, Andreas Meyer-Lindenberg, Jay Chang, Yuanyuan JiMichael F Egan, Terry E Goldberg, Joel E. Kleinman, Bai Lu, Daniel R Weinberger

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)509-18
Number of pages10
JournalNature Medicine
Volume15
Issue number5
DOIs
Publication statusPublished - May 2009

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Cerebral Cortex
  • Cognition
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • European Continental Ancestry Group
  • Gene Expression Regulation
  • Humans
  • Molecular Sequence Data
  • Neurons
  • Polymorphism, Single Nucleotide
  • Primates
  • Risk Factors
  • Schizophrenia
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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