ABSTRACT
The alpha7 neuronal nicotinic receptor gene (CHRNA7) has been implicated in the pathophysiology of schizophrenia by genetic and pharmacological studies. Expression of the alpha7* receptor, as measured by [(125)I]alpha-bungarotoxin autoradiography, is decreased in postmortem brain of schizophrenic subjects compared to non-mentally ill controls. Most schizophrenic patients are heavy smokers, with high levels of serum cotinine. Smoking changes the expression of multiple genes and differentially regulates gene expression in schizophrenic hippocampus. We examined the effects of smoking on CHRNA7 expression in the same tissue and find that smoking differentially regulates expression of both mRNA and protein for this gene. CHRNA7 mRNA and protein levels are significantly lower in schizophrenic nonsmokers compared to control nonsmokers and are brought to control levels in schizophrenic smokers. Sufficient protein but low surface expression of the alpha7* receptor, seen in the autoradiographic studies, suggests aberrant assembly or trafficking of the receptor.
Subject(s)
Gene Expression Regulation/drug effects , Genetic Predisposition to Disease/genetics , Nicotine/pharmacology , Receptors, Nicotinic/genetics , Schizophrenia/genetics , Smoking/genetics , Adult , Autoradiography , Brain Chemistry/drug effects , Brain Chemistry/genetics , Cohort Studies , Down-Regulation/genetics , Female , Genetic Markers/genetics , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/physiopathology , Humans , Male , Middle Aged , Protein Transport/genetics , Radioligand Assay , Receptors, Nicotinic/deficiency , Schizophrenia/metabolism , Schizophrenia/physiopathology , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
The alphaN-catenin (CTNNA2) gene represents a promising candidate gene for schizophrenia based upon previous genetic linkage, expression, and mouse knockout studies. CTNNA2 is differentially regulated by smoking in schizophrenic patients. In this report, the genomic structure of a primate-specific alphaN-catenin splice variant (alphaN-catenin III) is described. A comparison of alphaN-catenin III mRNA expression across postmortem hippocampi from schizophrenic and non-mentally ill smokers and non-smokers revealed a significant decrease in expression among patient non-smokers compared to all other groups. The recent evolutionary divergence of this gene, as well as the differences in gene expression in postmortem brain of schizophrenic non-smokers, supports the role of alphaN-catenin III as a novel disease susceptibility gene.
