Neurobiology of Dysbindin in Schizophrenia and sdy Mouse

描述（由申请人提供）：迄今为止，12项研究报告了dysbinding基因的某些单倍型与精神分裂症（SZ）之间的显著关联。Dysbindin最初被确定为肌营养不良蛋白的结合伙伴，肌营养不良蛋白是肌营养不良蛋白糖蛋白复合物的成员，存在于肌肉和大脑的突触后部位。随后的研究表明，dysbindin有其他的结合伙伴，包括block -1（溶酶体样细胞器复合物-1的生物发生）的几个成员。我们发现，在SZ海马形成的内在谷氨酸能投射的突触前区，dysbindin和几种block -1蛋白频繁且显著减少。异常结合蛋白的减少与谷氨酸转运蛋白的增加呈负相关。（VGluT-1）免疫反应性。这些改变发生时没有明显的突触丧失、（3-肌营养不良蛋白）的改变，也没有抗精神病药对结合不良蛋白或肌营养不良蛋白作用的证据

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.