Neuronal Adaptation and Plasticity after Chronic Disuse

摘要 兴奋性和突触功效的稳态调节与急性诱导的Hebbian效应一起起作用。 可塑性，以维持神经元放电在一定范围内，从而保持网络的稳定性和信息流。那里 内稳态可塑性可以影响内在特性（动作电位时程），这是一个普遍的共识 控制神经传递）或突触特性（例如，单一突触电流幅度），以及 涉及多种分子机制。体内平衡失调被认为是大脑 自闭症谱系障碍（ASD）等疾病。尽管付出了巨大的努力， 各种形式的稳态适应仍然不清楚。在这个项目中，我们将研究 与神经精神疾病相关的神经元内稳态。第一个问题是神经元 不活动启动突触后CaV 1通道附近的局部信号传导，并导致信号传播到突触后CaV 1通道。 细胞核调节mRNA选择性剪接（AS），从而影响尖峰持续时间。我们会把我们的发现 一个ASD相关基因（CACNA 1C，L型钙通道亚基）如何控制另一个基因的表达 （KCNMA 1，BK通道亚基）。我们的数据表明，通过bCaMKK（由 CAMKK 2）通过影响剪接因子Nova-2的定位在AS中起关键作用。在另一 子项目，我们将澄清如何相同的活动沉默影响突触的属性，和惊人的 突触后谷氨酸受体从Ca 2+不渗透性变为Ca 2+渗透性AMPA受体。 我们将破译各种信号通路，产生负反馈和正反馈， 协调触发衰减振荡响应的突触特性后TTX沉默，一种新的 我们集团的观察。我们将在体外培养的海马神经元上对循环回路的稳态进行研究 切片，使用全光学方法来可视化不活动后突触前权重的重新分配及其 突触后的后果每一个目标都与疾病状态相关，如ASD和 精神分裂症使用Timothy综合征的小鼠模型，一种罕见的ASD形式，我们将探索如何 在致病环境中改变生理现象，例如探索为什么不活动驱动的BK 剪接在蒂莫西综合征神经元中更为严重， 与ASD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.