Neurobiology of Dysbindin in Schizophrenia and sdy Mouse

描述(由申请人提供)：到目前为止，有12项研究报告了异常结合素基因中的某些单倍型与精神分裂症(SZ)之间的显著关联。Dystrobindin最初被确定为dystrobrevins的结合伙伴，dystrobrevins是dystrophin糖蛋白复合体的成员，存在于肌肉和脑中的突触后部位。随后的工作表明，dybindin有更多的结合伙伴，包括BLOC-1(溶酶体样细胞器复合体的生物发生-1)的几个成员。我们发现，在深圳大鼠海马区内源性谷氨酸能投射的突触前区域，dybindin和几个BLOC-1蛋白的表达频繁且显著减少。结合素的减少与囊泡谷氨酸转运体的增加呈负相关-！(VGluT-1)在相同投射中的免疫反应。这些改变发生时没有明显的突触丢失，没有3-dystrobrevin的改变，也没有证据表明抗神经药对dybindin或 VGluT-1我们建议在死后的SZ脑和Sandy(SDY)小鼠中研究dybindin，Sandy(SDY)是一种在dybindin基因中存在较大缺失突变的小鼠品系。我们的具体目标旨在回答有关SZ中异常结合素减少的一般性、原因和后果的关键问题，重点是它在谷氨酸传递中的作用。在目标1中，我们绘制了SZ中异常结合蛋白减少的区域分布和异构体特异性，并将其与几个神经递质系统的标记物相关联。在目的2中，我们研究了异常结合蛋白基因的表达及其与SZ高危单倍型的关系。在目标3中，我们测试了减少的dybindin对其BLOC-1结合伙伴的影响，以及通过减少dybindin改变谷氨酸能突触机制和谷氨酸释放的假想机制。在目标4中，我们使用高分辨率的电压敏感染料成像和全细胞斑片和现场记录在SDY小鼠的海马区结构中，研究了异常结合素负突变对谷氨酸能通路的神经传递、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.