Deciphering the Roles of Kainate Receptors in Developing CNS Circuits

总结 红藻氨酸受体信号传导对于中枢神经系统的适当发育是必需的。儿童 具有从头功能丧失或错义突变的患者表现出智力残疾和其他严重的 发育表型为什么会发生这种情况是未知的，部分原因是我们没有一个明确的 了解异常红藻氨酸受体功能如何破坏神经发育。这一目标 项目是（i）深入了解红藻氨酸受体发挥的正常神经发育作用，以及（ii） 确定当红藻氨酸受体信号传导异常时电路和行为中断的性质， 在小鼠模型中完全消失。我们将通过小鼠的比较研究来实现这些目标， 对已知的导致人类疾病的遗传变异进行建模。其中包括在 Swanson实验室，GluK2（A657T），在Grik2基因中模拟人类从头错义突变 导致智力残疾（ID）和共济失调的小鼠，以及模型Grik 2单倍不足的小鼠， 与人类群体中的发育迟缓和ID相关。Swanson & Savas公司 实验室将使用这些小鼠来测试红藻氨酸受体建立适当平衡的假设， 在海马回路的发育中，兴奋和抑制之间的联系，是正确发展 突触，并调节中枢神经系统的内在兴奋性。在第一个具体目标中，我们将确定如何 Grik2中的错义或功能丧失突变改变了突触连接、功能、形态和 突触和非突触蛋白质组在与行为改变相关的大脑区域中的表达。在 第二个具体目标，我们确定内在兴奋性是如何改变红藻氨酸受体突变小鼠。在 第三个具体目标，我们将对红藻氨酸受体突变小鼠进行行为学研究，以确定 广泛的认知，社会，习惯和运动功能障碍，这也将告知生理学研究， 目标1和2。我们预计这些研究将揭示一些潜在的电路中断，导致 人类认知和运动表型。因此，我们的目标是制定一个全面和综合的 了解红藻氨酸受体信号对建立适当神经元功能的重要性 在中枢神经系统，并建立如何异常信号导致适应不良的发展和行为的小鼠， 与人类发育障碍的核心症状相关。

SUMMARY Kainate receptor signaling is required for the appropriate development of the central nervous system. Children with de novo loss-of-function or missense mutations exhibit intellectual disability and other severe developmental phenotypes. Why this occurs is unknown, in part because we do not have a clear understanding of how aberrant kainate receptor function disrupts neural development. The objectives of this project are to (i) gain insight into normal neurodevelopmental roles played by kainate receptors and (ii) to determine the nature of circuit and behavioral disruptions when kainate receptor signaling is aberrant or completely lost in mouse models. We will pursue these objectives using comparative studies in mice that model known genetic variants causative for human disorders. These include a new mouse line generated in the Swanson laboratory, GluK2(A657T), that models a human de novo missense mutation in the Grik2 gene that causes intellectual disability (ID) and ataxia, as well as mice which model Grik2 haploinsufficiency which is associated with developmental delay and ID in human populations. The Contractor, Swanson and Savas laboratories will use these mice to test the hypotheses that kainate receptors establish an appropriate balance between excitation and inhibition in developing hippocampal circuits, are required for correct development of synapses, and regulate intrinsic excitability in the CNS. In the first Specific Aim, we will determine how missense or loss-of-function mutations in Grik2 alter synaptic connectivity, function, morphology and expression of the synaptic and non-synaptic proteome in brain regions associated with altered behaviors. In the second Specific Aim, we determine how intrinsic excitability is altered in kainate receptor mutant mice. In the third Specific Aim, we will carry out behavioral studies on kainate receptor mutant mice to determine the expanse of cognitive, social, habitual, and motor dysfunction, which will also inform the physiological studies in Aims 1 and 2. We anticipate these studies will reveal some of the underlying circuit disruptions that give rise to human cognitive and motor phenotypes. We therefore aim to develop a comprehensive and integrated understanding of the importance of kainate receptor signaling to establishment of appropriate neuronal function in the CNS and establish how aberrant signaling leads to maladaptive development and behaviors in mice that are correlates of the core symptoms of human developmental disorders.