Modulation of Entorhinal Cortex Neurons by Adenosine and Implications in TLE

描述(由申请人提供)： 腺苷在调节内嗅皮层(EC)第二层神经元兴奋性中起关键作用，腺苷对癫痫组织兴奋性的调节作用更大，这一假设将在从对照组大鼠以及我们的颞叶癫痫(TLE)大鼠模型中获得的脑片中进行验证。本实验将研究在对照和癫痫状态下腺苷对ECⅡ层神经元固有动作电位和突触驱动动作电位放电的调节能力，并通过两个特定的目的探讨这种差异性调制的机制：1.在我们的TLE大鼠模型中，验证腺苷介导的EC II层神经元固有动作电位和突触驱动动作电位放电的调制改变的假设。2.在我们的TLE大鼠模型中验证腺苷受体亚型在EC II层神经元中表达模式改变的假设。初步数据表明，与对照脑片相比，我们的TLE大鼠模型中EC II层神经元是过度兴奋的。数据还显示，腺苷能够从对照组织抑制EC Layer II神经元的固有和突触驱动的动作电位放电，而在对照组织中对EC Layer II神经元无效的腺苷浓度足以抑制我们的TLE大鼠模型EC Layer II神经元的动作电位放电。电生理记录将被用来检测这些神经元的放电特性以及腺苷应用对这些神经元兴奋性的影响，比较对照和TLE条件下的作用。将进行原位杂交和免疫组织化学实验，以检测腺苷受体亚型在两种情况下在EC中的表达谱和水平，以确定差异调节的机制。 公共卫生相关性： 这项研究将有助于我们理解TLE，特别是关于EC发生的变化，EC是海马体的主要输入区。研究腺苷在调节这一区域兴奋性中的作用可能会导致一种更有效的方法来抑制TLE的癫痫发作活动。

DESCRIPTION (provided by applicant): The hypothesis that adenosine plays a key role in modulating entorhinal cortex (EC) layer II neuronal excitability and that there is a greater modulation of excitability in epileptic tissue by adenosine will be tested in brain slices obtained from control rats as well from our rat model of temporal lobe epilepsy (TLE). The proposed experiments will study adenosine's ability to modulate both intrinsic and synaptically driven action potential firing in EC layer II neurons in the control and epileptic condition and investigate the mechanisms that mediate this differential modulation through two specific aims: 1. Test the hypothesis that adenosine mediated modulation of intrinsic and synaptically driven action potential firing of EC layer II neurons is altered in our rat model of TLE. 2. Test the hypothesis that adenosine receptor subtype expression patterns are altered in EC layer II neurons in our rat model of TLE. Preliminary data suggest that EC layer II neurons are hyperexcitable in our rat model of TLE as compared to control slices. Data also reveals that adenosine is able to inhibit both intrinsic and synaptically driven action potential firing in EC layer II neurons from control tissue and that concentrations of adenosine that are ineffective in modulating EC layer II neurons in control tissue are sufficient to inhibit action potential firing in EC layer II neurons from our rat model of TLE. Electrophysiological recordings will be used to examine the firing properties of these neurons and the effect that adenosine application has on the excitability of these neurons, comparing the actions between the control and TLE conditions. In situ hybridization and immunohistochemistry experiments will be carried out in order to examine the expression profile and levels of adenosine receptor subtypes in the EC in both conditions to determine the mechanism underlying the differential modulation. PUBLIC HEALTH RELEVANCE: This research will contribute to our understanding of TLE, specifically in regards to changes that occur in the EC, the main input area to the hippocampus. Examination of the role of adenosine in modulating excitability in this area could lead to a more effective way of inhibition seizure activity in TLE.