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

GABA 转运蛋白 GAT-3 在调节海马网络兴奋性中的作用

• 批准号: MR/P025641/1
• 负责人: Matthew Walker
• 金额: $ 60.73万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP025641%2F1
• 关键词: Role; GABA; transporter; GAT; regulating

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.

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于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是重要的。事实上，儿童时期长时间的抽搐对海马体造成的损害是耐药性癫痫最常见的原因，为了使海马体正常运作，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微妙的平衡。了解这两个过程如何工作可以帮助理解神经系统疾病的表现和如何治疗它们。整个大脑都有神经细胞和神经胶质。神经细胞相互沟通，对大脑活动至关重要。胶质细胞曾经被认为是大脑的“粘合剂”，并且只起支持作用。然而，神经科学的一个主要的最新进展是认识到胶质细胞在大脑活动中也起着关键作用，并且也可以相互之间以及与神经元进行“交流”。胶质细胞可以通过称为GAT3的GABA转运蛋白调节海马中的GABA，而且我们最近发现GAT3的激活可以导致其他化学物质的释放，这些化学物质可以改变海马的功能。这项研究探讨了GAT3的这些不同作用如何相互补充，以及GAT3如何控制海马体中的抑制作用。此外，我们还将探讨修饰GAT3活性是否可用于治疗癫痫。解决这些问题至关重要，因为GAT3是一种可药用靶点，可用于治疗从癫痫到阿尔茨海默病的一系列神经和神经退行性疾病。

项目成果

Commonalities in epileptogenic processes from different acute brain insults: Do they translate?

• DOI: 10.1111/epi.13965
• 发表时间: 2018-01
• 期刊: Epilepsia
• 影响因子: 5.6
• 作者: Klein P;Dingledine R;Aronica E;Bernard C;Blümcke I;Boison D;Brodie MJ;Brooks-Kayal AR;Engel J Jr;Forcelli PA;Hirsch LJ;Kaminski RM;Klitgaard H;Kobow K;Lowenstein DH;Pearl PL;Pitkänen A;Puhakka N;Rogawski MA;Schmidt D;Sillanpää M;Sloviter RS;Steinhäuser C;Vezzani A;Walker MC;Löscher W
• 通讯作者: Löscher W