EXCITATORY INNERVATION OF A SEIZURE INHIBITING NUCLEUS

癫痫抑制核的兴奋性神经支配

基本信息

批准号：
2750913
负责人：
John William Swann
金额：
$ 16.45万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-08-01 至 2000-07-31
项目状态：
已结题

项目摘要

Epilepsy is commonly thought to reflect one of 3 alterations in brain: l) excessive excitatory mechanisms, 2) diminished inhibitory mechanisms, or c) a combination of these. However, preliminary results, involving a model of experimentally induced audiogenic seizure (AGS) susceptibility, suggest increases in inhibitory mechanisms probably occur along with increases in excitatory innervation of inferior colliculus (IC), the site of seizure initiation. This suggests it is the balance between altered levels of both excitation and inhibition which determines pathogenic outcome. Such distinction is of heuristic importance because if the balance could be tipped toward inhibition, the epileptic brain might be rendered less prone to seizures. Certain neonatal treatments appear to have this effect. For example, preliminary results indicate rats experiencing a single seizure as neonates have less severe seizures as adults -- suggesting induction occurs of compensatory inhibitory brain circuitry. It is a putative site-specific increase in inhibition which we wish to study. AGS susceptibility appears to be due to an excitatory hyperinnervation of IC resulting from neonatal hearing deprivation. This abnormal experience appears to prevent the normal developmental use- and NMDA receptor- dependent regression of exuberant excitatory synapses in IC. However, in susceptible rats, the Dorsal nucleus of Lateral Lemniscus (DnLL), has now been found to also exhibit broader patterns of Fos-immunoreactive excitatory responses, suggesting it is also relatively hyperinnervated after hearing deprivation. The DnLL provides 55% of GABAergic inhibition in IC, and probably gates AGS severity by a feedforward inhibitory mechanism. Indeed, transection of GABAergic efferents between DnLL and IC greatly exacerbates seizure severity. We hypothesize excitatory innervation of DnLL also arises by a use- and NMDA receptor-dependent process, but that exuberance of innervation reduces, rather than promotes seizure responses. It is proposed to examine the role of DnLL in AGS severity, the normal development of its excitatory innervation, and whether such development can be selectively altered. Proposed studies focus on behavioral, functional, and anatomical alterations as a function of age, and in adults as a function of neonatal treatments. Neuron tracing and reconstruction techniques will address whether excessive branching of axonal arbors occurs in DnLL's after various neonatal treatments. The principle suggested here, that strength of feedforward inhibition can be selectively and developmentally manipulated, may result in new approaches to the treatment of epilepsies of childhood onset.

癫痫通常被认为反映了大脑的三种改变之一：l) 过度兴奋机制，2) 抑制机制减弱，或 c) 这些的组合。然而，初步结果涉及实验诱导听源性癫痫（AGS）易感性模型，表明抑制机制的增加可能与下丘（IC）的兴奋性神经支配增加，该部位癫痫发作的开始。这表明这是改变之间的平衡决定致病性的兴奋和抑制水平结果。这种区别具有启发意义，因为如果平衡可能会倾向于抑制，癫痫大脑可能是使癫痫发作的可能性降低。某些新生儿治疗似乎有这个效果。例如，初步结果表明大鼠经历一次癫痫发作，因为新生儿癫痫发作较轻成人——表明代偿性抑制脑的诱导发生电路。这是一种假定的位点特异性抑制增加，我们希望学习。 AGS 易感性似乎是由于兴奋性神经过度支配所致新生儿听力丧失导致的 IC。这种不正常的经历似乎会阻止正常发育使用和 NMDA 受体 IC 中旺盛的兴奋性突触的依赖性回归。然而，在易受影响的大鼠，外侧丘系背核（DnLL）现已被发现还表现出更广泛的 Fos 免疫反应模式兴奋反应，表明它也是相对神经过度支配的听力剥夺后。 DnLL 提供 55% 的 GABA 抑制在 IC 中，可能通过前馈抑制来控制 AGS 的严重程度机制。事实上，DnLL 和 IC 之间 GABA 能传出神经的横断大大加剧癫痫发作的严重程度。我们假设兴奋 DnLL 的神经支配也由使用和 NMDA 受体依赖性引起过程，但神经支配的旺盛会减少而不是促进癫痫发作反应。建议研究 DnLL 在 AGS 中的作用严重程度、兴奋性神经支配的正常发展，以及是否可以有选择地改变这种发展。拟议的研究关注行为、功能和解剖学的功能改变年龄，以及成人作为新生儿治疗的函数。神经元追踪和重建技术将解决是否过度各种新生儿出生后，DnLL 中会出现轴突乔木的分支治疗。这里建议的原则是，前馈的强度抑制可以被选择性地和发育地操纵，可能会导致治疗儿童期癫痫的新方法。