Maladaptive compensatory plasticity in developing cortical circuits

包括自闭症谱系障碍和智力残疾在内的发育障碍可导致 皮质活动减少奇怪的是，这些同样的疾病也大大增加了发展的风险。 癫痫发作多种稳态可塑性机制可以通过增加大脑的活动来补偿活动的减少。 兴奋性突触传递和细胞兴奋性，和/或通过减少抑制性突触传递。 但这些通常有益的机制可能会产生适应不良的影响，特别是当活动减少时。 在电路形成的关键时期，延迟和早期发生。例如，在体内阻断活性， 大鼠或小鼠的新皮层，诱导癫痫发作，但只有当它发生在早期和延长的时间。这里我们 探讨这种适应不良的补偿可塑性（MCP）的机制，在培养的新皮层 切片活动封锁在随后持续的同步活动中产生质的变化 当活动恢复时，这是伴随着一个戏剧性的转变， 兴奋和抑制之间的平衡。生理学和影像学研究表明， 突触连接性的改变。目的1将确定MCP的关键生理特征，将其分离 正常的自我平衡可塑性通过阻断单个神经元的活动， 活动阻断的持续时间，我们将区分细胞自主网络效应，并确定 对MCP的持续作用至关重要。使用突触成像技术和配对记录，我们问， MCP的诱导是否改变功能性兴奋性和抑制性突触的数量。 目的2发展了推/拉转录调控稳态可塑性的新思想。我们 鉴定一对密切相关的转录因子（TF），其被有效地和进行性地上调 在封锁活动期间。有趣的是，这些转铁蛋白是对抗代偿性可塑性的途径的一部分， 因为当它们被敲除时，补偿反应被夸大了。基于CRISPR的操作将 用于选择性改变特定细胞类型中TF的表达。RNAseq将用于识别候选人 染色质分析将区分直接和间接靶标。最后，我们将启动体内研究， 更直接地测试稳态可塑性及其转录调控在听源性癫痫发作中的作用。 总之，这些研究可能会确定新的战略，以减轻适应不良的后果，正常 有益的可塑性机制。

Developmental disorders including Autism Spectrum Disorders and Intellectual Disability can lead to reduced cortical activity. Paradoxically, these same disorders also greatly increase the risk for developing seizures. Multiple homeostatic plasticity mechanisms can compensate for reduced activity by increasing excitatory synaptic transmission and cellular excitability, and/or by decreasing inhibitory synaptic transmission. But these normally beneficial mechanisms can have maladaptive effects, especially when reduced activity is prolonged and occurs early, during a critical period of circuit formation. For example, activity blockade in vivo in rat or mouse neocortex, induces seizures, but only if it occurs early and for a prolonged period. Here we explore the mechanisms underlying this Maladaptive Compensatory Plasticity (MCP) in cultured neocortical slices. Activity blockade produces a qualitative change in subsequent synchronized activity that persists following prolonged deprivation when activity is restored. This is accompanied by a dramatic shift in the balance between excitation and inhibition. Physiological and imaging studies are consistent with a dramatic change in synaptic connectivity. Aim 1 will identify the critical physiological features of MCP, that separate it from normal homeostatic plasticity. By blocking activity in single neurons, and by varying the timing and duration of activity blockade, we will distinguish cell autonomous from network effects, and determine which are critical for persistent effects of MCP. Using synapse imaging techniques and paired recording, we ask whether induction of MCP alters the number of functional excitatory and inhibitory synapses. Aims 2 develops the novel idea of push/pull transcriptional regulation of homeostatic plasticity. We identify a pair of closely related transcription factors (TFs) that are potently and progressively upregulated during blockade of activity. Intriguingly, these TFs are part of a pathway that opposes compensatory plasticity, since compensatory responses are exaggerated when they are knocked out. CRISPR-based manipulations will be used to alter TF expression selectively in specific cell types. RNAseq will be used to identify candidate targets, and chromatin assays will distinguish direct and indirect targets. Finally, we will initiate in vivo studies to more directly test the role of homeostatic plasticity and its transcriptional regulation in audiogenic seizures. Together these studies may identify new strategies for mitigating maladaptive consequences of normally beneficial plasticity mechanisms.