Access

You are not currently logged in.

Access your personal account or get JSTOR access through your library or other institution:

login

Log in to your personal account or through your institution.

If You Use a Screen Reader

This content is available through Read Online (Free) program, which relies on page scans. Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.

Variation in GRM3 Affects Cognition, Prefrontal Glutamate, and Risk for Schizophrenia

Michael F. Egan, Richard E. Straub, Terry E. Goldberg, Imtiaz Yakub, Joseph H. Callicott, Ahmad R. Hariri, Venkata S. Mattay, Alessandro Bertolino, Thomas M. Hyde, Cynthia Shannon-Weickert, Mayada Akil, Jeremy Crook, Radha Krishna Vakkalanka, Rishi Balkissoon, Richard A. Gibbs, Joel E. Kleinman, Daniel R. Weinberger and Mortimer Mishkin
Proceedings of the National Academy of Sciences of the United States of America
Vol. 101, No. 34 (Aug. 24, 2004), pp. 12604-12609
Stable URL: http://www.jstor.org/stable/3373030
Page Count: 6
  • Read Online (Free)
  • Subscribe ($19.50)
  • Cite this Item
Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Variation in GRM3 Affects Cognition, Prefrontal Glutamate, and Risk for Schizophrenia
Preview not available

Abstract

GRM3, a metabotropic glutamate receptor-modulating synaptic glutamate, is a promising schizophrenia candidate gene. In a family-based association study, a common GRM3 haplotype was strongly associated with schizophrenia (P = 0.0001). Within this haplotype, the A allele of single-nucleotide polymorphism (SNP) 4 (hCV11245618) in intron 2 was slightly overtransmitted to probands (P = 0.02). We studied the effects of this SNP on neurobiological traits related to risk for schizophrenia and glutamate neurotransmission. The SNP4 A allele was associated with poorer performance on several cognitive tests of prefrontal and hippocampal function. The physiological basis of this effect was assessed with functional MRI, which showed relatively deleterious activation patterns in both cortical regions in control subjects homozygous for the SNP4 A allele. We next looked at SNP4′s effects on two indirect measures of prefrontal glutamate neurotransmission. Prefrontal N-acetylaspartate, an in vivo MRI measure related to synaptic activity and closely correlated with tissue glutamate, was lower in SNP4 AA homozygotes. In postmortem human prefrontal cortex, AA homozygotes had lower mRNA levels of the glial glutamate transporter EAAT2, a protein regulated by GRM3 that critically modulates synaptic glutamate. Effects of SNP4 on prefrontal GRM3 mRNA and protein levels were marginal. Resequencing revealed no missense or splice-site SNPs, suggesting that the intronic SNP4 or related haplotypes may exert subtle regulatory effects on GRM3 transcription. These convergent data point to a specific molecular pathway by which GRM3 genotype alters glutamate neurotransmission, prefrontal and hippocampal physiology and cognition, and thereby increased risk for schizophrenia.

Page Thumbnails

  • Thumbnail: Page 
[12604]
    [12604]
  • Thumbnail: Page 
12605
    12605
  • Thumbnail: Page 
12606
    12606
  • Thumbnail: Page 
12607
    12607
  • Thumbnail: Page 
12608
    12608
  • Thumbnail: Page 
12609
    12609