NEUROTRANSMITTER MECHANISMS IN EPILEPSY

这一续订申请建议继续检查神经机制 遗传性癫痫模型中的全身性癫痫发作 癫痫易感大鼠(GEPR)。GEPR表现出高度的易感性 电击、点燃、惊厥药物和 体温过高以及对听源性癫痫(AGS)的高度敏感性。 我们实验室和其他实验室之前的研究表明，强烈的神经元 增强的下丘(IC)神经元的放电 兴奋性氨基酸(EaAs)的可用性和GABA介导的减少 抑制发生在GEPR的AGS期间。这项提议将试图 明确核团神经元在癫痫传播网络中的作用 GEPR中的AGS以及这些部位的神经递质的作用。这 将涉及核团神经元放电异常的检查。 同步记录的AGS通路及其变化的相关性 行为。初步结果表明，异常突然和强烈的 放电的增加发生在IC的背侧皮质和网状结构 队形。AGS网络核团的神经递质机制 将通过微量注射药物来评估，这些药物增强了 GABA或减少EaAs进入AGS途径核内的作用 超越IC。初步结果表明，作用于GABA和EAA的药物 受体在其中几个部位有效地降低了AGS的严重程度 在GEPR中。然而，竞争性的NMDA拮抗剂大大降低了IC 神经元反应，而非竞争性NMDA拮抗剂作用最小 对IC神经元的影响，提示这些药物影响 不同的大脑部位。内源性GABA和EaAs释放在脑缺血再灌注损伤中的作用 在AGS期间，这些细胞核将通过以下药物的管理进行检查 影响这些氨基酸的水平。在这些地方观察到的异常现象 非听觉部位可能有助于解释 综合癫痫易发状态的GEPR。最近的研究表明 每天重复服用AGS会导致癫痫发作显著增加 GEPR中癫痫样脑电活动的严重程度。我们的预赛 结果表明，内侧膝状体(MGB)对此至关重要。 癫痫发作严重程度增加。这项建议将评估单个神经元 GEPR中IC到MGB通路的放电和行为变化 是每天癫痫发作的结果。初步结果表明，IC发射 随着AGS的重复大大增加。圆满完成这些目标 应该对神经元和神经递质有重要的洞察力 这种自然发生的全身性癫痫发作模型的机制 可能在阐明癫痫发生和增加的机制方面有价值。 我们对新潜能的作用机制和作用部位的知识 抗惊厥药。

This renewal application proposes to continue examining neural mechanisms of generalized seizures in an inherited epilepsy model, the genetically epilepsy-prone rat (GEPR). The GEPR exhibits heightened susceptibility to seizure induction by electroshock, kindling, convulsant drugs and hyperthermia as well as exquisite sensitivity to audiogenic seizures (AGS). Previous studies from our lab and others have shown that intense neuronal firing in inferior colliculus (IC) neurons mediated by increased availability of excitant amino acids (EAAs) and reductions in GABA-mediated inhibition occur during AGS of the GEPR. This proposal will attempt to define the role of neurons in nuclei in the seizure propagation network for AGS in the GEPR and the role of neurotransmitters in these sites. This will involve an examination of neuronal firing abnormalities in nuclei of the AGS pathway and correlation of changes with simultaneously recorded behavior. Preliminary results indicate that abnormally abrupt and intense rises in firing occur in the dorsal cortex of IC and in the reticular formation. Neurotransmitter mechanisms in the nuclei of the AGS network will be evaluated by microinjection of agents that enhance the action of GABA or decrease the action of EAAs into the nuclei of the AGS pathway beyond IC. Preliminary results indicate that agents acting at GABA and EAA receptors are effective in several of these sites in reducing AGS severity in the GEPR. However, the competitive NMDA antagonists greatly decrease IC neuronal response, while the non-competitive NMDA antagonists exert minimal effects on IC neurons, suggesting that these agents affect neurons in different brain sites. The role of endogenous release of GABA and EAAs in these nuclei during AGS will be examined by administration of agents that affect levels of these amino acids. The abnormalities observed in these non-auditory sites may help to explain the mechanisms that subserve the comprehensive epilepsy-prone state of the GEPR. Recent studies indicate that repetitive daily AGS results in a significant increase in seizure severity with epileptiform EEG activity in the GEPR. Our preliminary results suggest that the medial geniculate body (MGB) is crucial to this seizure severity increase. This proposal will evaluate single neuron firing and behavior changes in the IC to MGB pathway in the GEPR that results from daily seizures. Preliminary results indicate the IC firing greatly increases with AGS repetition. Successful completion of these aims should yield significant insight about neuronal and neurotransmitter mechanisms in this naturally-occurring model of generalized seizures that may be valuable in elucidating mechanisms of epileptogenesis and increase our knowledge of the mechanisms and sites of action of new potential anticonvulsant.