Alpha7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin 1.
Studies in cell culture and in animals suggest that neuregulin 1 (NRG1), a probable schizophrenia susceptibility gene, regulates the expression of the alpha7 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 alpha7 receptor levels. We examined the effects of four disease-associated single-nucleotide polymorphisms (SNPs) in the 5' region of the NRG1 gene on nAChR alpha7 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 alpha7 mRNA expression in the DLPFC. Haplotypes containing the risk alleles at the above SNPs were also associated with lower expression of nAChR alpha7 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 [(125)I] alpha-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 alpha7 expression.
Mathew
Shiny V
SV
Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, MD 20892-1385, USA.
Law
Amanda J
AJ
Lipska
Barbara K
BK
Dávila-García
Martha I
MI
Zamora
Eduardo D
ED
Mitkus
Shruti N
SN
Vakkalanka
Radhakrishna
R
Straub
Richard E
RE
Weinberger
Daniel R
DR
Kleinman
Joel E
JE
Hyde
Thomas M
TM
D000483:Alleles; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D015536:Down-Regulation; D015870:Gene Expression; D014644:Genetic Variation; D006239:Haplotypes; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020890:Neuregulin-1; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D012559:Schizophrenia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor