α7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin

Shiny V. Mathew, Amanda J. Law, Barbara K. Lipska, Martha I. Dávila-García, Eduardo D. Zamora, Shruti N. Mitkus, Radhakrishna Vakkalanka, Richard E. Straub, Daniel Weinberger, Joel Kleinman, Thomas Hyde

Research output: Contribution to journalArticle

Abstract

Studies in cell culture and in animals suggest that neuregulin 1 (NRG1), a probable schizophrenia susceptibility gene, regulates the expression of the α7 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 α7 receptor levels. We examined the effects of four disease-associated single-nucleotide polymorphisms (SNPs) in the 5′ region of the NRG1 gene on nAChR α7 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 α7 mRNA expression in the DLPFC. Haplotypes containing the risk alleles at the above SNPs were also associated with lower expression of nAChR α7 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] α-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 α7 expression.

Original languageEnglish (US)
Pages (from-to)2921-2932
Number of pages12
JournalHuman Molecular Genetics
Volume16
Issue number23
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

Fingerprint

Neuregulins
Neuregulin-1
Nicotinic Receptors
Prefrontal Cortex
Messenger RNA
Schizophrenia
Brain
Alleles
Single Nucleotide Polymorphism
Haplotypes
Bungarotoxins
Autoradiography
Genes
Real-Time Polymerase Chain Reaction
Hippocampus
Protein Isoforms
Down-Regulation
Cell Culture Techniques
Genotype
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

α7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin. / Mathew, Shiny V.; Law, Amanda J.; Lipska, Barbara K.; Dávila-García, Martha I.; Zamora, Eduardo D.; Mitkus, Shruti N.; Vakkalanka, Radhakrishna; Straub, Richard E.; Weinberger, Daniel; Kleinman, Joel; Hyde, Thomas.

In: Human Molecular Genetics, Vol. 16, No. 23, 01.12.2007, p. 2921-2932.

Research output: Contribution to journalArticle

Mathew, Shiny V. ; Law, Amanda J. ; Lipska, Barbara K. ; Dávila-García, Martha I. ; Zamora, Eduardo D. ; Mitkus, Shruti N. ; Vakkalanka, Radhakrishna ; Straub, Richard E. ; Weinberger, Daniel ; Kleinman, Joel ; Hyde, Thomas. / α7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin. In: Human Molecular Genetics. 2007 ; Vol. 16, No. 23. pp. 2921-2932.
@article{eb58c88bcba443d89d660152306e13d8,
title = "α7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin",
abstract = "Studies in cell culture and in animals suggest that neuregulin 1 (NRG1), a probable schizophrenia susceptibility gene, regulates the expression of the α7 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 α7 receptor levels. We examined the effects of four disease-associated single-nucleotide polymorphisms (SNPs) in the 5′ region of the NRG1 gene on nAChR α7 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 α7 mRNA expression in the DLPFC. Haplotypes containing the risk alleles at the above SNPs were also associated with lower expression of nAChR α7 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] α-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 α7 expression.",
author = "Mathew, {Shiny V.} and Law, {Amanda J.} and Lipska, {Barbara K.} and D{\'a}vila-Garc{\'i}a, {Martha I.} and Zamora, {Eduardo D.} and Mitkus, {Shruti N.} and Radhakrishna Vakkalanka and Straub, {Richard E.} and Daniel Weinberger and Joel Kleinman and Thomas Hyde",
year = "2007",
month = "12",
day = "1",
doi = "10.1093/hmg/ddm253",
language = "English (US)",
volume = "16",
pages = "2921--2932",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "23",

}

TY - JOUR

T1 - α7 nicotinic acetylcholine receptor mRNA expression and binding in postmortem human brain are associated with genetic variation in neuregulin

AU - Mathew, Shiny V.

AU - Law, Amanda J.

AU - Lipska, Barbara K.

AU - Dávila-García, Martha I.

AU - Zamora, Eduardo D.

AU - Mitkus, Shruti N.

AU - Vakkalanka, Radhakrishna

AU - Straub, Richard E.

AU - Weinberger, Daniel

AU - Kleinman, Joel

AU - Hyde, Thomas

PY - 2007/12/1

Y1 - 2007/12/1

N2 - Studies in cell culture and in animals suggest that neuregulin 1 (NRG1), a probable schizophrenia susceptibility gene, regulates the expression of the α7 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 α7 receptor levels. We examined the effects of four disease-associated single-nucleotide polymorphisms (SNPs) in the 5′ region of the NRG1 gene on nAChR α7 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 α7 mRNA expression in the DLPFC. Haplotypes containing the risk alleles at the above SNPs were also associated with lower expression of nAChR α7 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] α-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 α7 expression.

AB - Studies in cell culture and in animals suggest that neuregulin 1 (NRG1), a probable schizophrenia susceptibility gene, regulates the expression of the α7 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 α7 receptor levels. We examined the effects of four disease-associated single-nucleotide polymorphisms (SNPs) in the 5′ region of the NRG1 gene on nAChR α7 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 α7 mRNA expression in the DLPFC. Haplotypes containing the risk alleles at the above SNPs were also associated with lower expression of nAChR α7 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] α-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 α7 expression.

UR - http://www.scopus.com/inward/record.url?scp=35748953728&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35748953728&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddm253

DO - 10.1093/hmg/ddm253

M3 - Article

C2 - 17884806

AN - SCOPUS:35748953728

VL - 16

SP - 2921

EP - 2932

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 23

ER -