Research increasingly suggests that nitric oxide (NO) plays a role in the pathogenesis of schizophrenia. One important line of evidence comes from genetic studies, which have repeatedly detected an association between the neuronal isoform of nitric oxide synthase (nNOS or NOS1) and schizophrenia. However, the pathogenetic pathways linking nNOS, NO, and the disorder remain poorly understood. A deficit in sensorimotor gating is considered to importantly contribute to core schizophrenia symptoms such as psychotic disorganization and thought disturbance. We selected three candidate nNOS polymorphisms (Ex1f-VNTR, rs6490121 and rs41279104), associated with schizophrenia and cognition in previous studies, and tested their association with the efficiency of sensorimotor gating in healthy human adults. We found that risk variants of Ex1f-VNTR and rs6490121 (but not rs41279104) were associated with a weaker prepulse inhibition (PPI) of the acoustic startle reflex, a standard measure of sensorimotor gating. Furthermore, the effect of presence of risk variants in Ex1f-VNTR and rs6490121 was additive: PPI linearly decreased with increasing number of risk alleles, being highest in participants with no risk allele, while lowest in individuals who carry three risk alleles. Our findings indicate that NO is involved in the regulation of sensorimotor gating, and highlight one possible pathogenetic mechanism for NO playing a role in the development of schizophrenia psychosis.

Department of Behavioural Neuroscience Institute of Normal and Pathological Physiology Centre of Experimental Medicine Slovak Academy of Sciences Bratislava Slovakia

Department of Behavioural Neuroscience Institute of Normal and Pathological Physiology Centre of Experimental Medicine Slovak Academy of Sciences Bratislava Slovakia; Institute of Mathematics and Statistics Faculty of Science Masaryk University Brno Czech Republic

Department of Behavioural Neuroscience Institute of Normal and Pathological Physiology Centre of Experimental Medicine Slovak Academy of Sciences Bratislava Slovakia; Social Cognitive and Affective Neuroscience Unit Department of Basic Psychological Research and Research Methods Faculty of Psychology University of Vienna Vienna Austria

Department of Molecular Biology Faculty of Natural Sciences Comenius University in Bratislava Bratislava Slovakia

Institute of Molecular Biomedicine Faculty of Medicine Comenius University in Bratislava Bratislava Slovakia

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Absence of a significant interaction of two common NOS1 and 5-HTT polymorphisms on sensorimotor gating in humans