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.BackgroundDelayed 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.ObjectivesThe 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 StrategyAll 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. Programme(s) IC-INTAS - International Association for the promotion of cooperation with scientists from the independent states of the former Soviet Union (INTAS), 1993- Thème(s) 4 - Life Sciences INTAS - INTAS 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 Voir sur la carte Coût total Aucune donnée Participants (3) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire National Academy of Sciences of Ukraine Ukraine Contribution de l’UE Aucune donnée Adresse Bogomoletz str., 4 252024 Kiev Voir sur la carte Coût total Aucune donnée Russian Academy of Sciences Russie Contribution de l’UE Aucune donnée Adresse 142292 Pushchino, Moscow Region Voir sur la carte Coût total Aucune donnée Universite Paris Sud France Contribution de l’UE Aucune donnée Adresse 91504 Orsay Voir sur la carte Coût total Aucune donnée