内侧颞叶癫痫是成年人最为常见的顽固型癫痫。内嗅皮层和海马体是其发病的起始部位，但发病机制不详。T-type钙离子通道在动作电位阈值下被激活,直接调节细胞的兴奋性。我们曾首次报道，内嗅皮层中大量表达功能性T-type钙离子通道。在预实验中我们还发现在癫痫潜伏期，内嗅皮层T-type 钙离子通道调节的电流（T-currents）明显增加。由此，我们假设"内嗅皮层T-currents增加，直接增加神经细胞的兴奋性，从而导致癫痫的发病"可能是颞叶癫痫发病的新机制。本研究拟采用卡英酸颞叶癫痫模型，通过应用膜片钳电生理记录、双光子钙离子成像和谷氨酸释放等方法，从分子、细胞兴奋性及整体不同层次证明T-type钙离子通道的表达与颞叶癫痫的发病之间的关系。最后，申请人还将在癫痫潜伏期应用选择性T-currents阻断剂，从而评估是否可以延缓或中止癫痫病的发病，为颞叶癫痫的预防和治疗提供新的思路和新靶点。

Medial temporal lobe epilepsy (MTLE) is the most common, drug resistant form of epilepsy in adults. One of the characteristic features of this syndrome is the latent period which is a delay between the precipitating insults (such as traumatic head injury, status epilepticus et al. ) and the onset of spontaneous behavioral seizures. It is during this period that the cellular and network level changes leading to chronic MTLE occur. Thus, therapeutic intervention during this period could be beneficial in delaying the onset of chronic MTLE. Entorhinal cortex (EC) and hippocampus are the principle brain regions involved in the induction and maintenance of MTLE. In human, seizure can initiate in the EC and propagate to the hippocampus. In addition, during latent period the EC in vivo and in vitro has been shown to be hyperexcitable. However, the molecular mechanism by which MTLE onset is initiated in the EC is still not clear. Low-voltage-activated T-type calcium channels open at sub-threshold membrane potentials and it is ideal for them to regulate the threshold and firing pattern of action potentials. Thus, They play an important role in regulating neuronal excitability. We have first shown that functional T-type calcium channels are present in the EC (Huang et al.(2011)Nat Neurosci 14(4):478-86). In addition,our preliminary data suggested that T-type calcium channels mediated currents (T-currents) are significantly enhanced in the EC during latent period. Therefore, we proposed that the enhancement in T-currents increases neuronal excitability in the EC,thereby facilitates the development of MTLE and leads the onset of spontaneous epilepsy. To test this hypothesis, we will use patch-clamping, two-photon calcium imaging and glutamate uncaging techniques combined with pharmacological, immunological and molecular biological tools to investigate the role of T-type calcium channels in MTLE. Besides, we will utilize the selective T-type calcium channels blockers, TTA-P2 and TTA-A2, to block T-currents in latent period to assess if we can decay or stop the onset of MTLE. This study will uncover the fundamental causes of MTLE and thus identify possible therapeutic target.