Neuronal Adaptation and Plasticity after Chronic Disuse

摘要 兴奋性和突触效能的动态平衡调节与急性诱导的Hebbian共同作用 可塑性，以保持神经元的放电在限制范围内，从而保持网络的稳定性和信息流。那里 是否普遍同意动态平衡可塑性会影响固有特性(动作电位时程 控制神经传递)或突触特性(例如，单一突触电流幅度)和 涉及不同的分子机制。功能失调的动态平衡被认为是大脑的基础 自闭症谱系障碍(ASD)等疾病。尽管付出了巨大的努力，但这种病毒的分子基础 各种形式的动态平衡适应仍然不清楚。在这个项目中，我们将研究以下各个方面 神经元内稳态与神经精神障碍的相关性。第一个问题是神经元是如何 不活动启动突触后CaV1通道附近的局部信号，并导致信号传播到 细胞核调节选择性的mRNA剪接(AS)，从而影响峰持续时间。我们将扩大我们的发现 一个ASD相关基因(CACNA1C，L型钙通道亚基)如何控制另一个基因的表达 (KCNMA1，BK通道亚基)。我们的数据表明，通过bCaMKK(编码为 CAMKK2)通过影响剪接因子Nova-2的定位而在AS中发挥关键作用。在另一个国家 子项目，我们将阐明相同的活动沉默是如何影响突触特性的，以及显著的 突触后谷氨酸受体从钙离子不通透到钙离子通透的AMPA受体的转换。 我们将破译不同的信号通路是如何产生负反馈和正反馈的 一种新的TTX沉默后触发突触特性的抑制振荡反应的协调 我们小组的观察。我们将研究培养的海马区循环回路的动态平衡。 切片，使用全光学方法可视化不活动后突触前权重的重新分配及其 突触后后果。每个目标都与ASD和ASD等疾病状态相关 精神分裂症。利用一种罕见的ASD--Timothy综合征的小鼠模型，我们将探索 生理现象在致病环境中被改变，例如，探索为什么缺乏运动驱动BK 剪接在Timothy综合征神经元中更为严重，并探索这如何影响更高阶 与自闭症相关的功能。

ABSTRACT 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 plasticity can affect intrinsic properties (action potential duration controlling neurotransmission) or synaptic properties (unitary synaptic current amplitude, for example) and involves diverse molecular mechanisms. Dysfunctional homeostasis has been invoked as a basis for brain diseases such as autism spectrum disorders (ASD). Despite major effort, the molecular underpinnings of various forms of homeostatic adaptation are still not 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 extend our findings on how one ASD-related gene (CACNA1C, L-type Ca2+ channel subunit) controls the expression of another (KCNMA1, BK channel subunit). Our data suggest that signaling to the nucleus via bCaMKK (encoded by CAMKK2) plays a critical role in AS through effects on localization of the splice factor Nova-2. In another subproject, we will clarify how the same activity silencing affects synaptic properties, and the striking switchover of postsynaptic glutamate receptors from Ca2+-impermeable to Ca2+-permeable AMPA receptors. We will decipher how various signaling pathways, generating both negative and positive feedback, work in coordination to trigger a damped oscillatory response of synaptic properties following TTX silencing, a novel observation from our group. We will take studies of homeostasis to recurrent circuits in cultured hippocampal slices, using an all-optical approach to visualize reallocation of presynaptic weights following inactivity and their postsynaptic consequences. Each of the Aims are of relevance to disease states such as ASD and schizophrenia. Using a mouse model of Timothy Syndrome, a rare form of ASD, we will probe how physiological phenomena are altered in a pathogenic setting, for example exploring why inactivity-driven BK splicing is much more severe in Timothy Syndrome neurons and probing how this affects higher order functions of relevance to ASD.