Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, ON, Canada, L8N 3Z5.
Schizophr Res. 2011 Aug;130(1-3):250-9. doi: 10.1016/j.schres.2011.05.017.
Synapsin II is a synaptic vesicle-associated phosphoprotein that has been implicated in the pathophysiology of schizophrenia. Studies have demonstrated reductions in synapsin II mRNA and protein in medial prefrontal cortical post-mortem samples from patients with schizophrenia, genetic associations between synapsin II and schizophrenia, and synapsin II protein regulation by dopamine receptor activation. Collectively, this research indicates a relationship between synapsin II dysregulation and schizophrenia; however, it remains unknown whether perturbations in synapsin II play a role in the pathophysiology of this disease. The aim of this project was to evaluate animals with selective knock-down of synapsin II in the medial prefrontal cortex. After continuous infusion of synapsin II antisense sequences, animals were examined for the presence of schizophrenic-like behavioral phenotypes and assessed on the response to clinically relevant antipsychotic drugs. Our results indicate that rats with selective reductions in medial prefrontal cortical synapsin II demonstrate deficits in sensorimotor gating (prepulse inhibition), reduced social behavior, and hyperlocomotion, which are corrected by the atypical antipsychotic drug olanzapine. Additionally, synapsin II knock-down disrupts serial search efficiency. These behavioral changes are accompanied by reductions in vesicular neurotransmitter transporter protein concentrations for glutamate (VGLUT1 and VGLUT2) and GABA (VGAT), without affecting dopamine (VMAT2). These results implicate a causal role for decreased synapsin II in the medial prefrontal cortex in the pathophysiology of schizophrenia and the mechanisms of aberrant prefrontal cortical circuitry, and suggest that synapsin II may potentially serve as a novel therapeutic target for this disorder.
突触结合蛋白 II 是一种与突触小泡相关的磷酸化蛋白，与精神分裂症的病理生理学有关。研究表明，精神分裂症患者的中前额皮质死后样本中突触结合蛋白 II 的 mRNA 和蛋白质减少，突触结合蛋白 II 与精神分裂症之间存在遗传关联，以及多巴胺受体激活对突触结合蛋白 II 蛋白的调节。总的来说，这项研究表明突触结合蛋白 II 失调与精神分裂症之间存在关系；然而，突触结合蛋白 II 的紊乱是否在这种疾病的病理生理学中发挥作用仍不清楚。本项目的目的是评估中前额皮质选择性敲低突触结合蛋白 II 的动物。在连续输注突触结合蛋白 II 反义序列后，检查动物是否存在类似精神分裂症的行为表型，并评估对临床相关抗精神病药物的反应。我们的结果表明，中前额皮质选择性减少突触结合蛋白 II 的大鼠表现出感觉运动门控（前脉冲抑制）缺陷、社交行为减少和过度活跃，这些缺陷可被非典型抗精神病药物奥氮平纠正。此外，突触结合蛋白 II 的敲低会破坏连续搜索效率。这些行为变化伴随着谷氨酸（VGLUT1 和 VGLUT2）和 GABA（VGAT）的囊泡神经递质转运蛋白浓度降低，但不影响多巴胺（VMAT2）。这些结果表明，中前额皮质中突触结合蛋白 II 的减少与精神分裂症的病理生理学和异常前额皮质回路的机制有关，并表明突触结合蛋白 II 可能是这种疾病的一个新的治疗靶点。
