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A search for genes expressed in the adult and ageing brain during LTP, LTD and spatial learning

Objective



Learning and memory are essential aspects of cognitive function, and their decline in the dementias of old age presents a serious and growing social problem. Our aim is first to search for genes which are activated or suppressed during spatial learning in adult rats, and, secondly, to compare learning-related gene expression in normal and ageing rats, and thus to identify genes which are involved in the deterioration of cognitive function in senility. Long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus are types of activity-dependent synaptic plasticity which are thought to provide the physiological mechanism for information storage in the brain. It is likely, but not experimentally established, that the pattern of gene expression underlying synaptic plasticity and learning will be similar. A further aim of this project is to provide evidence for or against the hypothesis.
Objective 1. To identify and compare changes in gene expression in the rat hippocampus (i) following the induction of long term potentiation (LTP) and long-term depression (LTD), and (ii) after training in hippocampal-dependent spatial learning tasks.
Objective 2. To investigate how learning and plasticity-related changes in gene expression are affected by the process of ageing, with its attendant reduction in the duration of LTP and LTD, and impaired performance in spatial learning skills.
Objective 3. To identify the human homologues of learning and plasticity-related genes.
These objectives will be achieved in four, measurable stages: Stage 1. Identification of genes expressed in the hippocampus of freely-moving rats 2, 24 and 96 hours after the induction of LTP and LTD, using differential display and differential screening (subtractive library) techniques. Stage 2. Identification of genes that are expressed in the hippocampus of rats 24 hours after training in spatial memory tasks, using probes identified in stage 1.
Stage 3. Identification of the human homologues of rat genes expressed during synaptic plasticity and learning, by searching published human databases, and by construction of a high-quality cDNA library from human hippocampus Stage 4. Identification of changes in plasticity-related gene expression in advancing age, using probes identified in stage 1.
Our experiments will lead to the following results:
Result 1. An increase in understanding of the relationship between LTP/LTD and learning.
Result 2. Identification of novel genes associated with synaptic plasticity and cognition in the adult and ageing brain
Result 3. The identification of human homologues of rodent plasticity-related genes, a precondition for the development of genetic therapies of senile dementias.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

SmithKline Beecham Pharmaceuticals Ltd.
Address
Coldharbour Road
CM19 5AD Harlow
United Kingdom

Participants (4)

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE
France
Address
Boulevard De L'hôpital 83 Cervi
75013 Paris
MRC National Institute for Medical Research
United Kingdom
Address
The Ridgeway Mill Hil
NW7 1AA London
University of Haifa
Israel
Address

31905 Haïfa
Université de Paris-Sud XI
France
Address

91405 Orsay