Early Life Seizures Disrupt Critical Period Plasticity

生命早期的癫痫发作会破坏关键期的可塑性

• 批准号: 8811309
• 负责人: Takao K Hensch
• 金额: $ 0.22万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811309
• 关键词: Acoustics; Address; Affect; Age; Antiepileptic Agents; Applications Grants; Area; Auditory; Auditory area; Autistic Disorder; Behavior; Benchmarking; Birth; Brain; Child; Childhood; Chronic; Cognition Disorders; Cognitive; Comorbidity; Development; Disease; Epilepsy; Epileptogenesis; Equilibrium; Event; Excitatory Synapse; Genetic; Genetic Models; Glutamate Receptor; Impaired cognition; Incidence; Inhibitory Synapse; Intellectual functioning disability; Intervention; Laboratories; Learning; Life; Maps; Measures; Mental disorders; Modification; Molecular; Molecular Target; Neurocognitive; Neurologic; Neurons; Patients; Predisposition; Process; Public Health; Recurrence; Relative (related person); Research; Role; Seizures; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Synapses; Synaptic plasticity; Syndrome; System; Time; Wild Type Mouse; adverse outcome; autistic behaviour; critical period; developmental disease; early childhood; in vivo; infancy; mouse model; neuropsychiatry; neurotransmission; postnatal; prevent; receptor function; synaptic function; synaptogenesis; transmission process

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.

描述（由申请人提供）：癫痫和智力残疾（ID），包括自闭症，通常在早期生活中相互共病。出生后早期发育的特征是突触可塑性和学习能力增强的“关键期”（CP）。如果癫痫 癫痫发作发生在快速突触发育的环境中，如CP期间的情况，存在过度诱导活动依赖性突触修饰（可塑性）以及破坏该年龄窗特有的正常兴奋性：抑制性平衡的可能性，并且这反过来可能影响脑发育和神经行为。这个提议的中心假设是，早期生命癫痫发作可以改变突触发生和网络可塑性，从而破坏随后的CP的各个方面。到目前为止，癫痫发作对CP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定量解决。我们将评估暴露于早期癫痫发作的动物体内音调饲养引起的听觉皮层CP（目的1）。接下来，我们将研究特定听觉皮层网络中抑制（Aim 2）和兴奋（Aim 3）的成熟如何对CP做出贡献，以及这如何被早期癫痫发作所改变。最后，我们将进行初步的原理验证实验，以测试癫痫发作诱导的听觉CP中断如何与癫痫发作诱导的神经行为缺陷相关，以及是否在2种自闭症综合征小鼠模型中控制癫痫发作。如果成功，这些实验将揭示治疗伴随早期癫痫发作的ID和自闭症的新治疗靶点。