TREH通过GAD67调控GABA循环在癫痫中的作用及机制研究

癫痫是一种神经元异常兴奋引起的严重脑部疾病，而神经回路兴奋性增高与兴奋/抑制性递质失衡相关，靶向抑制性递质γ-氨基丁酸（GABA）可以有效控制癫痫。海藻糖酶（TREH）主要表达在神经元，通过调节海藻糖水解影响代谢稳态。课题组前期研究发现调控TREH影响海马神经元抑制性突触传递并降低癫痫发作程度，但潜在机制尚不清楚。本研究通过免疫荧光和代谢组学等预实验发现TREH主要与抑制性神经元共定位并影响GABA生成，而谷氨酸脱羧酶67（GAD67）是脑内GABA合成最重要限速酶，结合文献，我们提出假设：TREH通过GAD67调控GABA循环影响神经元兴奋性和癫痫表型。本研究拟应用分子生物学、膜片钳、场电位等多种实验技术，明确GAD67在TREH调控GABA循环中的作用，并探讨其机制，从而揭示TREH调节癫痫发作的潜在分子机制。

Epilepsy is a serious brain disease caused by the abnormal excitation of neurons, and the increased excitability of neural circuits is related to the imbalance of excitatory/inhibitory transmitters. Targeting inhibition of transmitter γ-aminobutyric acid (GABA) can effectively control epilepsy. Trehalase (TREH) is mainly expressed in neurons and affects metabolic homeostasis by regulating trehalose hydrolysis. Our previous study found that regulating TREH affects the inhibitory synaptic transmission of hippocampal neurons and reduces the degree of seizures, but the underlying mechanism is still unclear. In this project, pre-experiments such as immunofluorescence and metabolomics found that TREH mainly co-localizes with inhibitory neurons and affects GABA production, and glutamate decarboxylase67 (GAD67) is the most important rate-limiting enzyme for GABA synthesis in the brain, combined with literature, We put forward the hypothesis: TREH regulates the GABA cycle through GAD67 to affect neuronal excitability and epilepsy phenotype. This study intends to apply various experimental techniques such as molecular biology, patch clamp, and field potential to clarify the role of GAD67 in the regulation of GABA cycle by TREH and explore its mechanism, to reveal the potential molecular mechanism of TREH in regulating seizures.