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: 8708230
• 负责人: Takao K Hensch
• 金额: $ 40.96万
• 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/8708230
• 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）：包括自闭症在内的癫痫和智力残疾（ID）通常在早期生活中彼此合并。早期产后发育的特征是增强的突触可塑性和学习的“关键时期”（CP）。如果癫痫 癫痫发作发生在快速突触发育的环境中，就像CP期间一样，有可能过度诱导活动依赖性突触修饰（可塑性）以及正常兴奋性的破坏：这种年龄段的抑制平衡，这反过来又可能影响大脑发育和神经狂行。该提议的核心假设是早期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。迄今为止，有限的癫痫发作对CP事件的影响的证据一直处于细胞和分子变化的水平，但在系统级别尚未在体内定量解决。我们将评估因暴露于早期癫痫发作的动物体内饲养的体内张力而导致的听觉皮质CP（AIM 1）。接下来，我们将研究特定听觉皮质网络中抑制（目标2）和激发（AIM 3）的成熟如何有助于CP，以及如何通过早期癫痫发作改变这种情况。最后，我们将执行初步证明实验，以测试癫痫发作诱导的听觉CP的破坏与癫痫发作诱导的神经行为缺陷的相关性，以及在2种自闭症综合征模型中的癫痫发作控制是否。如果成功，这些实验将揭示新的治疗靶标，以治疗早期癫痫发作的ID和自闭症。