Early Life Seizures Disrupt Critical Period Plasticity

描述（由申请人提供）：癫痫和智力障碍（ID），包括自闭症，在生命早期通常会同时出现。产后早期发育的特点是突触可塑性和学习能力增强的“关键期”（CP）。如果是癫痫病 癫痫发作发生在突触快速发育的情况下，就像 CP 期间的情况一样，有可能过度诱导活动依赖性突触修饰（可塑性）以及破坏该年龄窗口特有的正常兴奋性：抑制性平衡，这反过来可能会影响大脑发育和神经行为。该提议的核心假设是生命早期癫痫发作可以改变突触发生和网络可塑性，从而扰乱随后的 CP 的各个方面。迄今为止，癫痫发作对脑性瘫痪事件影响的有限证据是在细胞和分子变化水平上，但尚未在体内系统水平上进行定量研究。我们将评估早期癫痫发作的动物体内音调饲养产生的听觉皮层 CP（目标 1）。接下来，我们将研究特定听觉皮层网络中抑制（目标 2）和兴奋（目标 3）的成熟如何影响 CP，以及早期癫痫发作如何改变这一点。最后，我们将进行试点原理验证实验，以测试癫痫发作引起的听觉 CP 破坏如何与癫痫发作引起的神经行为缺陷相关，以及在 2 个自闭症综合征小鼠模型中癫痫发作是否得到控制。如果成功，这些实验将揭示治疗伴随生命早期癫痫发作的智力障碍和自闭症的新治疗靶点。

DESCRIPTION (provided by applicant): Epilepsy and intellectual disability (ID), including autism are often comorbid with one another in early life. Early postnatal development is characterized by a "critical period" (CP) of enhanced synaptic plasticity and learning. If epilepsy and seizures occur in the setting of rapid synaptic development, as is the case during the CP, there is the potential for excessive induction of activity dependent synaptic modification (plasticity) as well as disruption of the normal excitatory:inhibitory balance unique to this age window, and this in turn could affect brain development and neurobehavior. The central hypothesis of this proposal is that early life seizures can alter synaptogenesis and network plasticity, thereby disrupting aspects of the subsequent CP. To date, the limited evidence for an effect of seizure on CP events has been at the level of cellular and molecular changes, but has not been addressed quantitatively in vivo at a systems level. We will assess auditory cortical CP resulting from in vivo tone rearing in animals exposed to early life seizures (Aim 1). Next, we wil examine how the maturation of inhibition (Aim 2) and excitation (Aim 3) in specific auditory cortical networks contribute to the CP and how this is altered by early life seizures. Finally, we will perform pilot proof-of-principle experiments to test how seizure induced disruption of auditory CP correlates with seizure-induced neurobehavioral deficits, as well as whether seizure control in 2 mouse models of autism syndromes. If successful, these experiments will reveal new therapeutic targets for the treatment of ID and autism that accompany early life seizures.