The hippocampus has been implicated in memory acquisition in man and other mammals. Slice preparations of the hippocampus allow cellular studies of synaptic transmission and its long term potentiation (LTP), processes reminiscent of associative learning. Mechanisms underlying LTP are likely to involve presynaptic changes in the amount of transmitters released as well as postsynaptic changes in the receptors or the intracellular second messengers involved in transducing the signal. LTP may last for hours and its maintenance requires protein synthesis, indicating that the long term changes in synaptic efficacy may involve gene regulation and structural alterations of the synapse. Transcriptional regulators such as c-fos and zif 268 are found to be up regulated at the transcriptional level by electrical activities in different regions of the brain including the hippocampus. The transient increase of these transcriptional regulators are likely to be the first in a chain of events that lead to long term changes in the expression of genes coding for specific functional elements and structural components of the synapse. From studies of cultured PC12 neurons, it is apparent that some of the genes coding for transcriptional regulators (e.g. c-fos) are themselves regulated at the transcriptional level not only by electrical activities but also by nerve growth factor. These findings suggest that the trophic factors present in the adult brain are likely to control not only the survival of neurons and their processes but also the expression of some of the genes involved in synaptic plasticity. Conversely, receptors of neurotransmitters such as the serotonin receptor have been found to play a potential role in neurite outgrowth, and to stimulate cell growth and division. These new findings illustrate the convergence of """"""""functional"""""""" and """"""""developmental"""""""" studies. This convergence is particularly important in studies of learning and memory which may involve both functional and structural changes of neurons and synapses. The proposed study includes, on the one hand, identification and characterizations of molecules potentially involved in these processes, including transmitter receptors, channels, trophic factors and their receptors, and transcriptional regulators, and on the other hand, functional studies at the cellular level on LTP, and possible involvement of these molecules in LTP. This concerted effort, combining the different expertise of the five investigators in this group, allow the approach to the general questions concerning the basis of learning and memory in a manner that is beyond the reach of any one of these researchers.
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