Role of the GABA transporter, GAT-3, in regulating network excitability in the hippocampus

海马体是大脑的一部分，在记忆和学习中起着关键作用。海马体的损伤或功能障碍对包括阿尔茨海默病和癫痫在内的许多神经系统疾病的症状很重要。事实上，儿童期长时间抽搐对海马体的损害是耐药性癫痫最常见的原因。为了使海马正常运作，神经递质谷氨酸介导的兴奋和神经递质GABA介导的抑制之间存在着良好的平衡。了解这两个过程是如何工作的可以帮助理解神经系统疾病的表现以及如何治疗它们。整个大脑有神经细胞和神经胶质。神经细胞之间相互交流，对大脑活动至关重要。神经胶质曾被认为是大脑的“粘合剂”，起着纯粹的辅助作用。然而，神经科学最近的主要进展之一是认识到神经胶质细胞在大脑活动中也起着至关重要的作用，并且还可以相互之间以及与神经元之间进行“交流”。胶质细胞可以通过GABA转运体GAT3调节海马中的GABA，但我们最近也发现GAT3的激活可以导致释放其他改变海马功能的化学物质。这项研究询问GAT3的这些不同作用是如何相互补充的，以及GAT3如何控制海马体中的抑制作用。此外，我们将询问是否修改GAT3活性可用于治疗癫痫。解决这些问题至关重要，因为GAT3是一种可药物靶点，可用于治疗从癫痫到阿尔茨海默病等一系列神经和神经退行性疾病。

The hippocampus is a part of the brain that plays a key role in memory and learning. Damage to or dysfunction of the hippocampus is important for the symptoms of a number neurological diseases including Alzheimer's disease and epilepsy. Indeed, damage to the hippocampus from prolonged convulsions in childhood is the commonest cause of drug-resistant epilepsy.In order for the hippocampus to operate normally, there is a fine balance between excitation mediated by the neurotransmitter glutamate, and inhibition mediated by the neurotransmitter GABA. Understanding how these two processes work can help understand the manifestations of neurological disease and how to treat them.Throughout the brain there are nerve cells and glia. Nerve cells communicate with one another and are crucial for brain activity. Glia were once considered "the glue" of the brain and to play purely a supportive role. However, one of the major recent advances in neuroscience is the realisation that glia also play a critical role in brain activity and can also "communicate" to one another and to neurons.Glia can regulate GABA in the hippocampus by mean of a GABA transporter termed GAT3, but also we have recently discovered that activation of GAT3 can result in the release of other chemicals that modify hippocampal function. This research asks how do these different roles of GAT3 complement one another and how does GAT3 control inhibition in the hippocampus. In addition, we will be asking whether modifying GAT3 activity can be used to treat epilepsy.Addressing these questions is critical as GAT3 is a druggable target that could be used to treat a range of neurological and neurodegenerative conditions from epilepsy to Alzheimer's disease.