L-aspartate signalling in the brain

点击翻译按钮获取中文摘要

Programme overview:This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to undertake important applied biomedical research in partnership with industry. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice. Project:L-aspartate has been suggested as an excitatory neurotransmitter but, its contribution as an excitatory neurotransmitter has largely been discounted on favour of glutamate, the universally recognised excitatory amino acid neurotransmitter. By using a new biosensor for L-aspartate, we have discovered that the intracellular enzyme, asparagine synthetase (ASNS), which converts L-aspartate to L-asparagine, is a key determinant of extracellular aspartate. Blockade of ASNS leads to accumulation of extracellular L-aspartate and development of seizure-like activity in hippocampal brain slices via an NMDA-receptor dependent process. Human mutations of ASNS are linked to microcephaly, cognitive impairment and chronic epilepsy. Our data suggests that some of this phenotype could be due to excessive accumulation of L-aspartate.This project will continue our study of the mechanisms and circumstances of L-aspartate release in hippocampal and cortical brain slices, the effects of blockade of ASNS, and the identity of the transporters that mediate the removal of L-aspartate from the extracellular space. As defective function of ASNS is linked to epilepsy, L-aspartate release will be examined in tissue from both control and epileptic mice. Accumulation of extracellular L-aspartate results in the development of seizure activity via the NMDA receptor activation. By using potent and specific pharmacological tools, the NMDA receptor subtypes involved will be established. As certain NMDA receptor subtypes are expressed only on very specific cell types in the hippocampus, this important step will help to elucidate the cellular circuitry involved in L-aspartate induced seizure activity. By understanding the molecular mechanisms that control extracellular L-aspartate this project will provide new insight into its physiological actions and how disorders of asparate signalling can lead to epilepsy.