Deciphering the Roles of Kainate Receptors in Developing CNS Circuits

摘要 海人藻酸受体信号是中枢神经系统正常发育所必需的。儿童 新生功能丧失或错义突变表现为智力残疾和其他严重的 发育表型。为什么会发生这种情况还不得而知，部分原因是我们没有一个明确的 了解异常的红藻氨酸受体功能如何扰乱神经发育。这样做的目的是 项目是：(I)深入了解红藻氨酸受体在正常神经发育中的作用；(Ii) 确定红藻氨酸受体信号异常或异常时电路和行为中断的性质 完全迷失在老鼠模型中。我们将通过在小鼠身上进行比较研究来实现这些目标 已知的导致人类疾病的遗传变异的模型。其中包括生成的新鼠标行 斯旺森实验室，GluK2(A657T)，模拟了人类Grik2基因的从头错义突变 这会导致智力残疾(ID)和共济失调，以及建立Grik2单倍体功能不全模型的小鼠 与人类群体中的发育迟缓和ID有关。承包商，斯旺森和萨瓦斯 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说。 在发育的海马神经元中的兴奋和抑制之间，是正确发育所必需的 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错义或功能丧失突变改变突触连接、功能、形态和 与行为改变相关的脑区突触和非突触蛋白质组的表达。在……里面 第二个具体目标是，我们确定红藻氨酸受体突变小鼠的内在兴奋性是如何改变的。在……里面 第三个具体目标，我们将对海氨酸受体突变小鼠进行行为学研究，以确定 认知、社交、习惯和运动功能障碍，这也将使生理学研究在 目标1和目标2。我们预计这些研究将揭示导致 人类的认知和运动表型。因此，我们的目标是开发一个全面和综合的 理解红藻氨酸受体信号对建立适当的神经元功能的重要性 并确定异常信号如何导致小鼠的适应不良发育和行为 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.