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

Neural Plasticity, Nov 2017

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.

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

Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice Hua Yang,1 Mengjie Zhang,1 Jiahao Shi,1 Yunhe Zhou,1 Zhipeng Wan,1 Yicheng Wang,2 Yinghan Wan,2 Jun Li,2 Zhugang Wang,2 and Jian Fei1,2 1School of Life Science and Technology, Tongji University, Shanghai 200092, China 2Shanghai Engineering Research Center of Model Organisms (SRCMO/SMOC), Shanghai 201203, China Correspondence should be addressed to Jian Fei; nc.ude.ijgnot@iefj Received 29 June 2017; Revised 31 August 2017; Accepted 15 October 2017; Published 28 November 2017 Academic Editor: Depei Li Copyright © 2017 Hua Yang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. 1. 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]. (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 [7–9]. However, how the reduction of SNAP-25 level is involved in the pathological phenotype remains unknown. In the brain, SNAP-25 proteins are abundantly expressed in glutamatergic terminals, while relatively lower amounts of the protein are detectable in GABAergic terminals [10]. The primary role of SNAP-25 is a fundamental component of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE). Together with cell membrane protein syntaxin and vesicle-associated membrane protein (VAMP), SNAP-25 mediates presynaptic vesicle docking and exocytosis [11]. In addition to regulation of synaptic transmission, SNAP-25 is also believed to regulate intracellular calcium dynamics through negative modulation of voltage-gated calcium channels. It also plays a role in other neuronal processes, including spine morphogenesis, postsynaptic receptor trafficking, and neuronal plasticity [12]. But the underlying cellular mechanisms still need to be explored. Over the past few decades, several mouse models have been constructed to elucidate the physiological role of SNAP-25 in vivo. Complete knockout of SNAP-25 in mice leads to no evoked exocytosis and death of the animal at birth. However, heterozygous mice are able to survive and exhibit locomotor hyperactivity and learning deficiencies. SNAP-25 knock-in mice, which have a single amino acid substitution of Ala for Ser187, have been shown to display epilepsy and anxiety-related behavior. The blind-drunk (Bdr) mouse expresses a dominant point mutant SNAP-25b protein, resulting in impaired sensorimotor gating and ataxia, while SNAP-25b-deficient model has developmental defects, seizures, and impair (...truncated)


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Hua Yang, Mengjie Zhang, Jiahao Shi, Yunhe Zhou, Zhipeng Wan, Yicheng Wang, Yinghan Wan, Jun Li, Zhugang Wang, Jian Fei. Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice, Neural Plasticity, 2017, 2017, DOI: 10.1155/2017/4526417