Neuronal Adaptation and Plasticity after Chronic Disuse

 描述(由申请人提供)：兴奋性和突触功效的动态平衡调节与急性诱导的Hebbian可塑性相结合，将神经元的放电维持在一定范围内，从而保持网络的稳定性和信息流。人们普遍认为，稳态突触可塑性可以是全局的(神经元所有突触的均匀伸缩)，也可以是局部的(突触强度不是均匀伸缩的)，并可以由不同的分子机制调节。有趣的是，自闭症谱系障碍(ASD)等脑部疾病的基础是功能失调。尽管付出了很大努力，但不同形式的动态平衡适应的分子基础仍然不是很清楚。在这个项目中，我们将检查神经元稳态的各个方面与神经精神障碍的相关性。第一个问题是神经元不活动如何启动局部信号。 在突触后CaV1通道附近，导致信号传播到核，以调节选择性mRNA剪接(AS)，从而影响棘波持续时间。我们将了解一个ASD相关基因(CACNA1C，L型钙通道亚基)是如何控制另一个基因(KCNMA1，BK通道亚基)的表达的。我们的初步数据表明，通过βCaMKII和γCaMKII向细胞核发出的信号通过影响剪接因子Nova-2的定位在AS中发挥关键作用。在另一个涉及AMPACaMKII的子项目中，我们将阐明βCaMKII如何影响突触后谷氨酸受体的组成，以及从钙不通透到钙通透的β受体的惊人转换。突触后受体的变化和突触前功能之间的协调也将被研究，重点是逆行信号分子，如BDNF。我们将把我们的研究扩展到在培养的海马片的循环回路水平上的动态平衡，使用全光学方法来可视化假设的突触前重量在不活动后的重新分配。最后，我们会 探索为什么不活动驱动的BK剪接在Timothy综合征(一种罕见的ASD)小鼠模型中的神经元中更严重，从而将基因故障与与疾病状态相关的细胞效应联系起来。综上所述，我们的研究将阐明关键信号蛋白的稳态功能，并为异常稳态适应与ASD等神经元疾病之间的可能联系提供一种新的方法。

 DESCRIPTION (provided by applicant): Homeostatic regulation of excitability and synaptic efficacy works in conjunction with acutely induced Hebbian plasticity to maintain neuron firing within limits and thus preserve network stability and information flow. There is general agreement that homeostatic synaptic plasticity can be global (uniform scaling across all synapses of a neuron) or local (synaptic strength not uniformly scaled), and can be mediated by diverse molecular mechanisms. Interestingly, dysfunctional homeostasis has been invoked as a basis for brain diseases such as autism spectrum disorders (ASD). Despite major effort, the molecular underpinnings of diverse forms of homeostatic adaptation are still not very clear. In this project, we will examine various aspects of neuronal homeostasis with relevance to neuropsychiatric disorders. The first question is how neuronal inactivity initiates local signaling near postsynaptic CaV1 channels and causes propagation of signals to the nucleus to regulate alternative mRNA splicing (AS) and thus affect spike duration. We will find out how one ASD-related gene (CACNA1C, L-type Ca2+ channel subunit) controls the expression of another (KCNMA1, BK channel subunit). Our preliminary data suggest that signaling to the nucleus via βCaMKII and γCaMKII plays a critical role in AS, through effects on localization of the splice factor Nova-2. In another subproject involving βCaMKII, we will clarify how βCaMKII affects postsynaptic glutamate receptor composition, and a striking switchover from Ca2+- impermeable to Ca2+-permeable AMPA receptors. Coordination between changes in postsynaptic receptors and presynaptic function will also be investigated, with a focus on retrograde signaling molecules such as BDNF. We will extend our studies to homeostasis at the level of recurrent circuits in cultured hippocampal slices, using an all-optical approach to visualize a hypothesized reallocation of presynaptic weights following inactivity. Finally, we will explore why inactivity-driven BK splicing is more severe in neurons derived from a mouse model of Timothy Syndrome, a rare form of ASD, thereby connecting malfunction of genes to cellular effects of relevance to disease states. Taken together, our studies will clarify the homeostatic functions of key signaling proteins and offer a fresh approach to the possible links between the abnormal homeostatic adaptation and neuronal disorders like ASD.