Completed Brain & Nervous System Genetics & Molecular Biology

Discovering novel subtype-selective glutamate receptor antagonists for the study of hippocampal synaptic plasticity

Funder MRC (part of UKRI)
Recipient organisation University of Bristol
Funding £1.9M
Period Jan 2008 — Dec 2012

In plain English

AI plain-English summary

Every time you learn something new, a specific subtype of glutamate receptor in your brain is being switched on—and this project aims to build chemical tools that can block just that one subtype, leaving all others untouched. The problem is that glutamate, the brain’s main excitatory messenger, activates many different receptor subtypes at once, making it nearly impossible to tell which one does what. Without tools that can pick apart these subtypes, scientists cannot pin down the exact molecular steps that turn a fleeting signal into a lasting memory. This is a fundamental gap in our understanding of how the brain works. This is primarily curiosity-driven fundamental science. The immediate goal is not a drug or a therapy, but a set of chemical probes that let researchers ask precise questions about synaptic plasticity—the cellular basis of learning and memory. If successful, these tools could eventually help reveal why certain receptor subtypes malfunction in schizophrenia, Alzheimer’s, and Parkinson’s disease. Past work with similar receptor-selective compounds has already transformed neuroscience; this project aims to extend that precision to a family of receptors that has so far resisted it.

View original technical description
The main aim of this work is to design and synthesize new chemical substances to be used as tools to investigate the fundamental mechanism of learning and memory. This research may lead to new treatments for disorders that involve cognitive dysfunction, such as schizophrenia, Alzheimer’s and Parkinson’s disease. Communication between one nerve cell (neuron) and others in the brain is effected at the junctions (synapses). One of the main mechanisms by which one cell in a neuronal chain communicates with the next cell is by releasing an amino acid, glutamate from its multiple synaptic endings. We have helped establish that glutamate can interact with a family of structurally related proteins known as glutamate receptor subtypes each performing different functions in the central nervous system (CNS). Whereas glutamate activates all the subtypes of glutamate receptor, we aim to produce tools that block the activation of only one subtype of receptor. By observing what effect specific activation or blockade of a particular glutamate receptor subtype has on the functioning of the CNS, one can deduce the particular role of that receptor subtype in the integrated pattern of nervous activity that underlies learning and memory.

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Researchers

David Jane (Principal Investigator)David. Lodge (Co-Investigator)Elek Molnar (Co-Investigator)Graham Collingridge (Co-Investigator)Zafar Bashir (Co-Investigator)Zuner Bortolotto (Co-Investigator)

Related Research

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Original classification

Research Grant

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