Assessment of glutamate delta-1 receptor in mental disorders

描述(由申请人提供)：据估计，每110名儿童中约有1人患有自闭症谱系障碍(ASD)，对个人和家庭造成毁灭性的后果，同时也是经济负担。目前还没有有效的治疗ASD的方法，了解其潜在的机制可能有助于确定新的治疗靶点。人类全基因组关联研究已经确定了可能导致自闭症的遗传变异。这些研究已经证实，ASD相关基因是参与突触形成和信号传递的大型功能网络的一部分。然而，几个新确定的候选基因的确切生理作用仍然是 未知。谷氨酸受体离子型Delta-1(GRID1)基因编码谷氨酸三角洲-1(GluD1)亚基，是ASD和分裂性情感障碍的易感基因之一。据报道，在ASD和分裂情感障碍患者中也有较低的GluD1表达。此外，最近的研究已经确定了GluD1通过与突触前Neurexin1相互作用在突触形成中的潜在作用，Neurexin1本身就是自闭症的易感基因。这些一致的发现表明，GluD1可能是ASD中调节失调的功能性突触网络的一部分。我们的初步数据有力地表明，GluD1的缺失导致了几种类似于人类ASD患者缺陷的行为和分子异常。这项建议的目的是专门了解GluD1基因敲除小鼠这些异常行为的神经基础。为此，我们将确定GluD1缺失对小鼠脊柱形态和内侧前额叶皮质突触功能的影响，该功能调节已知受 ASD患者。我们还发现，NMDA受体激动剂D-环丝氨酸能够挽救GluD1基因敲除小鼠的社会缺陷。因此，我们将测试内侧前额叶皮质突触异常的逆转是否是D-环丝氨酸在社会缺陷中的疗效的基础。这些研究将为GluD1在调节突触结构和功能中发挥关键作用提供第一个证据，最终调节行为，并可能确定ASD的新治疗靶点。此外，我们的研究将支持这样的假设，即促进活动依赖机制可能在缓解ASD表型方面具有治疗价值。

DESCRIPTION (provided by applicant): It is estimated that ~1 in every 110 children is affected by autism spectrum disorders (ASDs) with devastating consequence to the individual and family along with being an economic burden. There is currently no effective therapy available for ASD and understanding the underlying mechanisms may lead to identification of novel therapeutic targets. Human genome-wide association studies have identified genetic variations that may contribute to ASDs. These studies have established that ASD-associated genes are part of a large functional network involved in synapse formation and signaling. However, the precise physiological role of several of the newly identified candidate genes is still unknown. GRID1 (Glutamate Receptor Ionotropic Delta-1) gene, which codes for the glutamate delta-1 (GluD1) subunit, is one such gene identified as a susceptibility gene for ASDs and schizoaffective disorders. Lower GluD1 expression has also been reported in ASD and schizoaffective disorder patients. Moreover, recent studies have identified a potential role of GluD1 in synapse formation via interaction with presynaptic Neurexin1, which itself is an autism susceptibility gene. These converging findings suggest that GluD1 may be a part of the functional synaptic network that is dysregulated in ASD. Our preliminary data strongly indicates that deletion of GluD1 leads to several behavioral and molecular abnormalities that resemble deficits in human ASD patients. The goal of this proposal is to specifically understand the neural basis of these abnormal behaviors in GluD1 knockout mice. Towards this end we will determine the effect of GluD1 deletion in mouse on spine morphology and synaptic function in the medial prefrontal cortex, which regulates social behaviors and cognitive abilities known to be affected in ASD patients. We have also found that an NMDA receptor agonist D-cycloserine is able to rescue social deficits in GluD1 knockout mouse. We will therefore test whether reversal of synaptic abnormalities in the medial prefrontal cortex underlie the efficacy of D-cycloserine in social deficits. These studies will provide the first evidence for a crucial role of GluD1 in the regulation of synaptic structure and function that eventually modulate behavior and potentially identify a novel therapeutic target for ASD. Additionally, our studies will support the hypothesis that facilitation of activity-dependent mechanisms may have therapeutic value in alleviating ASD phenotype.