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Contenu archivé le 2022-12-23

Mechanisms underlying cell death associated with neurological disorders: Identification and characterisation of pathological forms of neuronal plasticity.

Objectif

This research proposal is focused on the following hypothesis:
Abnormal, persistent potentiation of glutamate-mediated synaptic transmission is induced by transient insults to the brain, and promotes delayed neuronal death. Characterisation of persistent synaptic malfunctions will help to develop novel preventive and therapeutic strategies, to promote the survival of brain cells in patients with neurological disorders.
Background
Delayed or progressive neuronal death is associated with a number of crippling neurological disorders (e.g. stroke), and it contributes to motor and cognitive impairment in patients. Recent discoveries have shown that excessive excitation is damaging to neurones, and this neurotoxic mechanism is now termed excitotoxicity. Abnormal glutamate-mediated synaptic transmission is potentially excitotoxic because glutamate is the main excitatory neurotransmitter in the mammalian brain, and glutamate-receptor antagonists are cerebroprotective in various models of neurodegenerative disorders. However, which are the malfunctions of glutamate-mediated synapses contributing to brain cell death in patients with neurological diseases remains unclear.
Objectives
The main purpose of this project is to investigate two different forms of abnormal long-term potentiation (LTP) of glutamatergic synaptic transmission discovered recently by the NIS applicants. One type of LTP is triggered by transient ischaemia (ischaemia-LTP), and the other by repeated increases in the extracellular concentration of K+ (K-LTP). Both triggering insults are relevant to stroke, traumatic brain injury and epilepsy. NIS scientists will elucidate the molecular mechanisms underlying these persistent synaptic abnormalities. The INTAS member teams will ascertain that abnormal forms of LTP occur in vivo (e.g. in relevant models of neurological disorders), and examine their effect on the resistance of neurones to subsequent ischaemic or excitotoxic insults.
Experimental Strategy
All the work will be undertaken in the rat hippocampus, because this brain region is selectively vulnerable to ischaemia and excitotoxic insults, and abnormal forms of LTP have been identified in this area. The experimental strategy will be multidisciplinary, combining neurochemistry, state-of-the-art electrophysiology, and pharmacology. Mechanisms involved in the development and maintenance of abnormal LTP will be investigated in hippocampal slices where robust experimental methods can be applied. In vivo procedures will rely on innovative monitoring devices (e.g. microdialysis probes incorporating a recording electrode), which allow investigators to record electrophysiological variables while exposing the brain region under study to controlled changes and/or specific pharmacological agents.
The proposed research will undoubtedly advance our knowledge of biochemical abnormalities associated with insults to the brain and, therefore, help to identify new pharmacological strategies to promote neuronal survival and regeneration. Investigation into abnormal forms of LTP will also complement and strengthen our understanding of molecular mechanisms underlying learning and memory since these mental faculties involve physiological forms of LTP. Results will be published in major neuroscience journals and presented at scientific meetings dedicated to neuronal plasticity and/or neurodegeneration.

Appel à propositions

Data not available

Régime de financement

Data not available

Coordinateur

University of Bradford
Contribution de l’UE
Aucune donnée
Adresse
Richmond Road
BD7 1DP Bradford
Royaume-Uni

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Coût total
Aucune donnée

Participants (3)