SNARE Complex Dysfunction: A Unifying Hypothesis for Schizophrenia

Abstract

Schizophrenia is a debilitating psychiatric disorder that affects approximately 1% of the world’s population at tremendous personal, social, and economic costs. Individuals with schizophrenia exhibit diverse combinations of positive, negative, and cognitive symptoms. Genetic susceptibility and environmental stressors are major risk factors for schizophrenia, contributing to the variety of phenotypes. It has been widely hypothesized that deficiencies in neurotransmitter systems contribute to schizophrenia. The dopamine hypothesis was supported by observations that pharmacologically increasing dopamine (e.g., with amphetamine) can induce psychosis in humans, whereas antipsychotics that block dopamine alleviate the positive symptoms of schizophrenia. Similarly, the glutamate hypothesis arose from observations that schizophrenia was associated with decreased glutamate levels, and the administration of glutamate antagonists in healthy subjects induced psychosis. These two hypotheses are combined in a third hypothesis, the synaptic hypothesis, which proposes that general deficits in synaptic function are a root cause of schizophrenia ( 1 Johnson R.D. Oliver P.L. Davies K.E. SNARE proteins and schizophrenia: Linking synaptic and neurodevelopmental hypotheses. Acta Biochim Pol. 2008; 55: 619-628 PubMed Google Scholar ). In this issue of Biological Psychiatry, Ramos-Miguel et al. ( 2 Ramos-Miguel A. Beasley C.L. Dwork A.J. Mann J.J. Rosoklija G. Barr A.M. et al. Increased SNARE protein-protein interactions in orbitofrontal and anterior cingulate cortices in schizophrenia. Biol Psychiatry. 2015; 78: 361-373 Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar ) explore the hypothesis that presynaptic abnormalities in the neurotransmitter exocytic machinery are altered in schizophrenia. This hypothesis is intriguing because altered neurotransmitter release could yield problems with dopamine and glutamate signaling, synapse function, and neural development, all of which have been observed in individuals with schizophrenia. Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in SchizophreniaBiological PsychiatryVol. 78Issue 6PreviewSynaptic dysfunction in schizophrenia may be associated with abnormal expression or function of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins (syntaxin, synaptosomal-associated protein 25 [SNAP25], vesicle-associated membrane protein [VAMP]) forming the molecular complex underlying neurosecretion. The impact of such abnormalities on efficient SNARE heterotrimer formation is poorly understood. We investigated putative SNARE dysfunction, along with possible roles for the SNARE binding partners Munc18-1, complexins (Cplx) 1/2, and synaptotagmin in brains from autopsies of individuals with and without schizophrenia. Full-Text PDF