Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice.

Hua Yang,Mengjie Zhang,Yinghan Wan,Zhipeng Wan,Yunhe Zhou,Jiahao Shi,Zhugang Wang,Jian Fei,Yicheng Wang,Jun Li

doi:10.1155/2017/4526417

Abstract

Several studies have associated reduced expression of synaptosomal-associated protein of 25 kDa (SNAP-25) with schizophrenia, yet little is known about its role in the illness. In this paper, a forebrain glutamatergic neuron-specific SNAP-25 knockout mouse model was constructed and studied to explore the possible pathogenetic role of SNAP-25 in schizophrenia. We showed that SNAP-25 conditional knockout (cKO) mice exhibited typical schizophrenia-like phenotype. A significantly elevated extracellular glutamate level was detected in the cerebral cortex of the mouse model. Compared with Ctrls, SNAP-25 was dramatically reduced by about 60% both in cytoplasm and in membrane fractions of cerebral cortex of cKOs, while the other two core members of SNARE complex: Syntaxin-1 (increased ~80%) and Vamp2 (increased ~96%) were significantly increased in cell membrane part. Riluzole, a glutamate release inhibitor, significantly attenuated the locomotor hyperactivity deficits in cKO mice. Our findings provide in vivo functional evidence showing a critical role of SNAP-25 dysfunction on synaptic transmission, which contributes to the developmental of schizophrenia. It is suggested that a SNAP-25 cKO mouse, a valuable model for schizophrenia, could address questions regarding presynaptic alterations that contribute to the etiopathophysiology of SZ and help to consummate the pre- and postsynaptic glutamatergic pathogenesis of the illness.

Highlights

Schizophrenia (SZ), a complicated psychiatric disorder, affects almost 1 percent of the general population in the world [1, 2]
It has been documented that the synaptosomal-associated protein of 25 kDa (SNAP-25) is a candidate risk gene for SZ, as supported by the following lines of evidence: (1) Genetic association and linkage studies have revealed that chromosome region 20p12.2 which SNAP-25 locates in has significant linkage with SZ [4, 5]. (2) Large-scale genome-associated case-control studies have revealed that several single nucleotide polymorphisms (SNPs) of SNAP-25 are significantly associated with SZ [6]. (3) Various postmortem analyses have found that the expression of SNAP-25 is reduced in prefrontal cortex (PFC) and hippocampus in brain of patients with SZ [7,8,9]
Our results provided in vivo functional evidence to support that altered SNAP-25 expression in the forebrain glutamatergic neurons lead to a greater effect of the illness, confirming the strong association between SNAP-25 and SZ

Summary

Introduction

Schizophrenia (SZ), a complicated psychiatric disorder, affects almost 1 percent of the general population in the world [1, 2]. While the etiology and pathophysiology of SZ remain elusive, genetic risk factors are recognized as an important contributing factor to the pathogenesis of this neuropsychiatric disorder [3]. It has been documented that the synaptosomal-associated protein of 25 kDa (SNAP-25) is a candidate risk gene for SZ, as supported by the following lines of evidence: (1) Genetic association and linkage studies have revealed that chromosome region 20p12.2 which SNAP-25 locates in has significant linkage with SZ [4, 5]. In addition to regulation of synaptic transmission, SNAP-25 is believed to regulate intracellular calcium dynamics through negative modulation of voltage-gated calcium channels. It plays a role in other neuronal processes, including spine morphogenesis, postsynaptic receptor

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