Assessment of glutamate delta-1 receptor in mental disorders

描述（由申请人提供）：据估计，每110名儿童中就有1名患有自闭症谱系障碍（ASDs），这对个人和家庭造成了毁灭性的后果，同时也是一种经济负担。目前还没有有效的治疗ASD的方法，了解潜在的机制可能会导致新的治疗靶点的发现。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。这些研究表明，自闭症相关基因是突触形成和信号传导的一个大型功能网络的一部分。然而，一些新发现的候选基因的确切生理作用仍然是未知的

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.