Human Molecular Genetics Advance Access originally published online on September 20, 2007
Human Molecular Genetics 2007 16(23):2921-2932; doi:10.1093/hmg/ddm253
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin 1
1 Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1385, USA, 2 Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK and 3 Department of Pharmacology, Howard University College of Medicine, Washington, DC 20059, USA
* To whom correspondence should be addressed at: 10 Center Dr., Bldg 10, Room 4N312, Bethesda, MD 20892-1385, USA. Tel: +1-301-496-8848; Fax: +1-301-402-2751; Email: hydet{at}mail.nih.gov
Received June 6, 2007; Revised August 24, 2007; Accepted August 30, 2007
Studies in cell culture and in animals suggest that neuregulin 1 (NRG1), a probable schizophrenia susceptibility gene, regulates the expression of the 
7 nicotinic acetylcholine receptors (nAChRs). We hypothesized that schizophrenia-associated allelic variations within the NRG1 gene, via their effects on NRG1 isoform expression, would be associated with alterations in nAChR 7 receptor levels. We examined the effects of four disease-associated single-nucleotide polymorphisms (SNPs) in the 5' region of the NRG1 gene on nAChR 7 mRNA transcript expression in both the dorsolateral prefrontal cortex (DLPFC) and hippocampus of normal controls and patients with schizophrenia using quantitative real-time PCR. NRG1 risk alleles at SNPs SNP8NRG221132 and rs6994992 predicted significantly lower nAChR 7 mRNA expression in the DLPFC. Haplotypes containing the risk alleles at the above SNPs were also associated with lower expression of nAChR 7 in the DLPFC. The genotype effect for rs6994992 and the haplotype effect were more pronounced within the schizophrenic patient group. To determine whether receptor levels follow that of mRNA expression, we performed receptor binding and autoradiography using [125I] -bungarotoxin in the DLPFC. Consistent with the mRNA findings, we found a decrease in binding in risk allele carriers of SNP8NRG221132 as compared with heterozygous individuals. Together, these results suggest that the molecular mechanism of the association between NRG1 risk alleles and schizophrenia may include down-regulation of nAChR 7 expression.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. L. Hancock, S. E. Canetta, L. W. Role, and D. A. Talmage Presynaptic Type III Neuregulin1-ErbB signaling targets {alpha}7 nicotinic acetylcholine receptors to axons J. Cell Biol., October 14, 2008; 181(3): 511 - 521. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zhong, C. Du, M. Hancock, M. Mertz, D. A. Talmage, and L. W. Role Presynaptic Type III Neuregulin 1 Is Required for Sustained Enhancement of Hippocampal Transmission by Nicotine and for Axonal Targeting of {alpha}7 Nicotinic Acetylcholine Receptors J. Neurosci., September 10, 2008; 28(37): 9111 - 9116. [Abstract] [Full Text] [PDF]
|
|