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Regulated intramembrane proteolysis by [gamma]-secretase cleaves proteins in their transmembrane domain and is involved in important signaling pathways. At least four different [gamma]-secretase complexes have been identified, but little is known about their biological role and specificity. Previous work has demonstrated the involvement of the Aph1A-[gamma]-secretase complex in Notch signaling, but no specific function could be assigned to Aph1B/C-[gamma]-secretase. We demonstrate here that the Aph1B/C-[gamma]-secretase complex is expressed in brain areas relevant to schizophrenia pathogenesis and that Aph1B/C deficiency causes pharmacological and behavioral abnormalities that can be reversed by antipsychotic drugs. At the molecular level we find accumulation of Nrg1 fragments in the brain of [Aph1BC.sup.-/-] mice. Our observations gain clinical relevance by the demonstration that a Val-to-Leu mutation in the Nrg1 transmembrane domain, associated with increased risk for schizophrenia, affects [gamma]-secretase cleavage of Nrg1. This finding suggests that dysregulation of intramembrane proteolysis of Nrg1 could increase risk for schizophrenia and related disorders. Alzheimer's | knockout | schizophrenia | presenilin | prepulse inhibition