Sensorimotor gating is associated with CHRNA3 polymorphisms in schizophrenia and healthy volunteers

Abstract

Attentional gating deficits, commonly measured by prepulse inhibition (PPI) of the acoustic startle response (ASR), have been established as an endophenotype of schizophrenia. PPI is heritable and has been associated with polymorphisms in serotonin and dopamine system genes. PPI can be enhanced by nicotine, and therefore it has been proposed that schizophrenia patients smoke to ameliorate their early attentional deficits. The PPI-enhancing effects of nicotine in rodents are strain-dependent, suggesting a genetic contribution to PPI within the nicotinic acetylcholine receptor (nAChR) system. Recent human genetic studies also imply that tobacco dependence is affected by polymorphisms in the α3/α5 subunits of the nAChR (CHRNA3/CHRNA5) gene cluster. We therefore investigated the impact of two common CHRNA3 polymorphisms (rs1051730/rs1317286) on PPI, startle reactivity, and habituation of the ASR in two independent samples of 107 British healthy volunteers and 73 German schizophrenia patients. In both samples, PPI was influenced by both CHRNA3 polymorphisms (combined p-value 0.0027), which were strongly linked.. Moreover, CHRNA3 genotype was associated with chronicity, treatment, and negative symptoms in the schizophrenia sample. These results suggest that sensorimotor gating is influenced by variations of the CHRNA3 gene, which might also have an impact on the course and severity of schizophrenia.