Early Life Seizures Disrupt Critical Period Plasticity

描述(申请人提供)：癫痫和智力残疾(ID)，包括自闭症，通常在早期生活中彼此共存。出生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”。如果癫痫 而癫痫发作发生在突触快速发育的背景下，就像CP期间的情况一样，有可能过度诱导依赖活动的突触修饰(可塑性)以及破坏这个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。这一建议的中心假设是，早期生命癫痫可以改变突触发生和网络可塑性，从而扰乱随后CP的各个方面。到目前为止，癫痫发作对CP事件影响的证据有限，仅限于细胞和分子水平的变化，但还没有在体内系统水平上进行定量研究。我们将评估暴露在早期生命癫痫中的动物体内音调饲养所产生的听觉皮质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)的成熟如何对CP做出贡献，以及这是如何被早期生命癫痫发作改变的。最后，我们将进行初步的原理验证实验，以测试癫痫诱发的听觉CP中断与癫痫诱导的神经行为障碍之间的关系，以及两种自闭症小鼠模型的癫痫控制情况。如果成功，这些实验将揭示治疗伴随早期生命癫痫的ID和自闭症的新治疗目标。

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.