EAAC1 Transporter Associated Protein, GABA & Epilepsy

神经谷氨酸转运体EAAC1的表达降低可引起成年大鼠癫痫。最近的代谢研究表明，这种癫痫活动可能是由于GABA合成减少造成的，这表明EAAC1参与了正常的GABA代谢。这些结果为维持GABA递质库的细胞机制提供了新的见解。我们拟通过控制EAAC1在体内的活性，研究EAAC1对癫痫发作、谷氨酸摄取、GABA合成和突触抑制的影响，研究EAAC1摄取谷氨酸与癫痫之间的关系。最近，一种新的蛋白被鉴定和表征，它是EAAC1的内源性负调节因子。该蛋白GTRAP3-18 （Glutamate Transporter Associated protein 3-18）可能通过EAAC1介导的谷氨酸摄取作用，在GABA代谢调控中发挥关键作用。本项目的总体目标是确定(1)EAAC1表达降低是否会导致成年大鼠GABA合成减少而引起癫痫，(2)通过GTRAP3-18直接或间接干扰EAAC1代谢是否会破坏GABA的合成。这些关于EAAC1参与GABA代谢的研究可能会导致对癫痫病因的新见解，并有助于开发治疗各种癫痫性疾病的新治疗方法。意义：本研究旨在确定成人大脑中谷氨酸转运体EAAC1、GABA代谢和癫痫之间的关系。我们计划测试GTRAP3-18 （EAAC1活性的负调节因子）水平的升高是否会导致癫痫，或者降低GTRAP3-18表达是否会降低癫痫易感性。我们希望这些关于EAAC1摄取谷氨酸与gaba能传递功效之间联系的研究，可能有助于找到治疗癫痫的新方法。

Decreasing the expression of the neuronal glutamate transporter, EAAC1, causes epilepsy in adult rats. Recent metabolic studies indicate that this seizure activity may result from a reduced synthesis of GABA, implicating the involvement of EAAC1 in normal GABA metabolism. These results offer new insights about the cellular mechanisms responsible for maintaining the transmitter pool of GABA. We propose to investigate the relationship between glutamate uptake by EAAC1 and epilepsy, by manipulating EAAC1 activity in vivo, and examining the effect that this has on seizures, glutamate uptake, GABA synthesis, and synaptic inhibition. Recently, a novel protein was identified and characterized that is an endogenous negative regulator of EAAC1. This protein, GTRAP3-18 (Glutamate Transporter Associated Protein 3-18), may play a critical role in the regulation of GABA metabolism through its effect on glutamate uptake mediated by EAAC1. The overall goals of this project are to determine, (1) if decreasing EAAC1 expression decreases GABA synthesis and causes epilepsy in adult rat, (2) if interfering with EAAC1 metabolism directly or indirectly through GTRAP3-18 disrupts the synthesis of GABA. These studies of EAAC1 involvement in GABA metabolism may lead to new insights into the causes of epilepsies, and help to develop novel therapeutic approaches for treating a variety of seizure disorders. Significance: The studies proposed in this grant seek to define the relationship between the glutamate transporter EAAC1, GABA metabolism, and epilepsy in the adult brain. We plan to test whether an increase in the level of GTRAP3-18, a negative regulator of EAAC1 activity, causes epilepsy, and alternatively, whether decreasing GTRAP3-18 expression decreases seizure susceptibility. Our hope is that these studies of the links between glutamate uptake by EAAC1 and the efficacy of GABAergic transmission, may help to identify novel approaches for treating epilepsy.