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Physiological basis of learning and memory processes in the brain


The proposed project concerns synaptic plasticity in relation to learning and memory. This area of research is important both for human health and basic biomedical research. Memory is essential for human identity and our ability to function socially. Its loss is amongst the most devastating aspects of brain disorders such as epilepsy, stroke and Alzheimer's disease.

A better understanding of normal memory may lead to better treatment of memory disorders. Spike timing-dependent synaptic plasticity ( STDP) is a strong candidate mechanism, obeying the theoretical predictions made by Donald Hebb and sharing mechanisms with long-term potentiation (LTP) as well as long-term depression (LTD).

Two objectives are identified:
- To establish whether spike timing-dependent potentiation and depression can be dissociated by NMDA receptor-subunit-selective drugs, and
- to investigate the differences in Ca2+ transients induced by activation of these receptors.

The first objective would be met by conventional whole-cell patch-clamp recordings during current clamp from CA1 pyramidal neurones in rat hippocampal slices. The second objective would be met by Ca2+ imaging using confocal microscopy. Hippocampal LTP remains our best model of those synaptic changes that might underlie behavioural memory.

The recent discovery that distinct subunits of the NMDA receptor are necessary for induction of respectively LTP and LTD suggests a novel way to manipulate the conditions in ways that should favour either of these types of plasticity. We intend to use this approach to control the direction of plasticity and investigate the corresponding [Ca2+] changes.

If spike timing-dependent synaptic potentiation and depression can be dissociated pharmacologically, a more detailed investigation into their possible involvement during behavioural memory would be possible, as well as their possible involvement in brain disorders such as epilepsy and excitotoxicity.

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