Increased SNARE Protein-Protein Interactions in Orbitofrontal and Anterior Cingulate Cortices in Schizophrenia.

Abstract

BACKGROUND:

Synaptic 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.

METHODS:

Postmortem samples were obtained from orbitofrontal cortex (OFC) and/or anterior cingulate cortex from two separate cohorts (n = 15 + 15 schizophrenia cases, n = 13 + 15 control subjects). SNARE interactions were studied by immunoprecipitation and one- or two-dimensional blue native polyacrylamide gel electrophoresis (BN-PAGE).

RESULTS:

In the first cohort, syntaxin, Munc18-1, and Cplx1, but not VAMP, Cplx2, or synaptotagmin, were twofold enriched in SNAP25 immunoprecipitated products from schizophrenia OFC in the absence of any alterations in total tissue homogenate levels of these proteins. In BN-PAGE, the SNARE heterotrimer was identified as a 150-kDa complex, increased in schizophrenia samples from cohort 1 (OFC: +45%; anterior cingulate cortex: +44%) and cohort 2 (OFC: +40%), with lower 70-kDa SNAP25-VAMP dimer (-37%) in the OFC. Upregulated 200-kDa SNARE-Cplx1 (+65%) and downregulated 550-kDa Cplx1-containing oligomers (-24%) in schizophrenia OFC were identified by BN-PAGE. These findings were not explained by postmortem interval, antipsychotic medication, or other potentially confounding variables.

CONCLUSIONS:

The findings support the hypothesis of upregulated SNARE complex formation in schizophrenia OFC, possibly favored by enhanced affinity for Munc18-1 and/or Cplx1. These alterations offer new therapeutic targets for schizophrenia.

• Authors: Alfredo Ramos-Miguel, Clare L Beasley, Andrew J Dwork, J John Mann, Gorazd Rosoklija, Alasdair M Barr, William G Honer
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 78 Issue 6 Pg. 361-73 (Sep 15 2015) ISSN: 1873-2402 [Electronic] United States
• PMID: 25662103 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• Multiprotein Complexes
• SNARE Proteins

Topics

• Gyrus Cinguli (metabolism)
• Humans
• Multiprotein Complexes (metabolism)
• Prefrontal Cortex (metabolism)
• Presynaptic Terminals (metabolism)
• Prospective Studies
• Protein Binding
• SNARE Proteins (metabolism)
• Schizophrenia (metabolism)