Neurobiology of Dysbindin in Schizophrenia and sdy Mouse

描述（由申请人提供）：迄今为止，有12项研究报告了dysbindin基因的某些单倍型与精神分裂症（SZ）之间的显著关联。Dysbindin最初被鉴定为肌营养不良蛋白的结合伴侣，肌营养不良蛋白糖蛋白复合物的成员存在于肌肉和脑中的突触后位点。随后的工作表明，dysbindin有额外的结合伙伴，包括BLOC-1（溶酶体样细胞器复合物-1的生物发生）的几个成员。我们已经发现，dysbindin和几个BLOC-1蛋白质经常显着减少在突触前领域的内在神经元投射的海马结构在SZ。dysbindin的减少与囊泡谷氨酸转运蛋白的增加呈负相关。（VGluT-1）免疫反应性。这些改变的发生没有明显的突触丢失，β-dystrobrevin的改变，或对dysbindin或 VGluT-1我们建议调查dysbindin在死后SZ的大脑和桑迪（sdy）小鼠，一个大的dysbindin基因缺失突变的小鼠品系。我们的具体目标旨在回答有关SZ中dysbindin减少的一般性，原因和后果的关键问题，重点是其在谷氨酸传输中的作用。在目的1中，我们绘制了SZ中dysbindin减少的区域分布和亚型特异性，并将其与几种神经递质系统的标志物相关联。在目的2中，我们研究dysbindin基因表达及其与SZ高危单倍型的关系。在目标3中，我们测试了减少的dysbindin对其BLOC-1结合伴侣的影响，并假设了减少的dysbindin改变突触能突触机制和谷氨酸释放的机制。目的4：利用高分辨率电压敏感染料成像和全细胞斑片记录及场记录，研究dysbindin负性突变对海马结构神经传递、长时程增强和长时程抑制的影响。

DESCRIPTION (provided by applicant): Twelve studies to date report significant associations between certain haplotypes in the dysbindin gene and schizophrenia (SZ). Dysbindin was initially identified as a binding partner of the dystrobrevins, members of the dystrophin glycoprotein complex present in muscle and postsynaptic sites in the brain. Subsequent work has shown that dysbindin has additional binding partners, including several members of BLOC-1 (the biogenesis of lysosome-like organelles complex-1). We have found that dysbindin and several BLOC-1 proteins are frequently and significantly reduced in presynaptic fields of intrinsic glutamatergic projections of the hippocampal formation in SZ. The dysbindin reductions are inversely correlated with increased vesicular glutamate transporter-! (VGluT-1) immunoreactivity in the same projections. These alterations occur without apparent synaptic loss, alterations in (3-dystrobrevin, or evidence of neuroleptic effects on dysbindin or VGluT-1 We propose to investigate dysbindin in postmortem SZ brains and in the sandy (sdy) mouse, a mouse strain with a large deletion mutation in the dysbindin gene. Our specific aims are designed to answer key questions about the generality, causes, and consequences of dysbindin reductions in SZ with a focus on its role in glutamate transmission. In Aim 1, we map the regional distribution and isoform specificity of dysbindin reductions in SZ and correlate these with markers of several neurotransmitter systems. In Aim 2, we investigate dysbindin gene expression as well as its relation to high risk haplotypes for SZ. In Aim 3, we test the effects of reduced dysbindin on its BLOC-1 binding partners and hypothesized mechanisms by which reduced dysbindin alters glutamatergic synaptic machinery and glutamate release. In Aim 4, we use high resolution imaging of voltage-sensitive dyes and whole cell patch and field recordings in the sdy mouse hippocampal formation to investigate the effects of the dysbindin negative mutation on neurotransmission, long term potentiation and long term depression in glutamatergic pathways.