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Investigation of striatal soluble N-ethylmaleimide sensitive factor attachment receptor (SNARE) proteins in schizophrenia

University of British Columbia

Synaptic dysfunction likely contributes to abnormal brain function in schizophrenia. Patient symptoms indicate that the striatum is involved in this disease. The three neuronal soluble-NSF-attachment receptor (SNARE) proteins (SNAP-25, syntaxin-1 and VAMP) interact at the presynaptic neuronal membrane to facilitate neurotransmission, and are thus key players in synaptic function. SNARE abnormalities have already been reported in cortical and hippocampal brain regions in schizophrenia. Their involvement in striatal dysfunction has not been investigated. Normal synaptic function requires the SNAREs to physically interact with each other, but little is known about how altered SNARE protein levels in schizophrenia relate to SNARE protein interactions. Multiple isoforms of each SNARE exist in the brain, may affect SNARE protein interactions and synaptic transmission differently, and may diverge functionally. SNARE isoform expression in schizophrenia is unknown. Thus, abnormalities in SNARE protein expression or function may underlie or contribute to brain dysfunction and disease. In this thesis, SNARE protein levels were measured in human post mortem brain samples of schizophrenia subjects for the first time in the striatum. The functional consequences of SNARE alterations were investigated by developing a novel ELISA assay to measure SNARE protein interactions. The possible confounding effects of medications were addressed in several ways, including the use of striatal tissue from animals exposed to antipsychotic medications. Alterations in SNAP-25 and syntaxin-1 protein levels were further dissected by measuring protein isoforms. Syntaxin-1 isoforms were assayed by quantitative immunoblotting. A mass-spectrometry based assay was developed and used to measure SNAP-25 protein isoform levels. The results of these investigations suggest that SNARE protein alterations in schizophrenia are restricted to distinct functional regions of the striatum, perturb SNARE protein interactions, involve specific protein isoforms, and may occur independent of patient treatment with antipsychotic medications. Furthermore, these studies contribute a new, high-throughput method for measuring SNARE protein interactions, and for the first time, a means of detecting and quantifying SNAP-25 isoforms in brain tissue.

Text

2011-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/29150

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/