The focus of this proposal is on long-term potentiation (LTP) a form synaptic enhancement that is widely thought to be a critical cellular components of learning and memory. Impetus for this approach comes from studies showing that aged (24 mos) rats which have been reported to have learning and memory deficits also appear to have a significant impairment in their ability to develop LTP. In previous studies we and other have shown that protein kinase C (PKC) into CA1 pyramidal cells produces LTP- like potentiation while injection of peptide inhibitors of either PKC or CA2+/calmodulin kinase II (CAM kinased II) blocks induction of LTP. Thee have been few studies of the role of specific phosphoproteins LTP. However, recent studies have shown an excellent congruence of the function of certain specific phosphoproteins and some of the more salient characteristics of LTP. Good evidence indicates that LTP is associated with increased transmitter release and good evidence supports a role for the synapsing phosphoproteins in regulating neurotransmitter released. In addition, it is clear that protein kinase C plays an important role in at lease the post-synaptic aspects of LTP. Our recent work has shown that the GABAA receptor is a substrate for protein kineses C. Moreover, changes in GABAA receptor function have been linked to production of LTP by physiologically relevant stimulation. Thus our studies of LTP, aging and protein phosphorylation will focus on the synapsing proteins and the GABAA receptor. The first part of the proposal will consist of attempts to determine the mechanism(s) underlying the age-dependent defects in the norepinephrine- stimulated phosphorylation of the presynaptic proteins. We will also study the norepinephrine stimulated phosphorylation of the GABAA receptor as previous studies have shown age-related defects in GABAergic function. In addition to norepinephrine, we will look for age-related changes in electrophysiology and phosphorylation in response to other pharmacological treatments (e.g. activators of protein kinase C, elevated calcium) that have been shown to produce LTP-Like potentiation. Taken together, we feel that these experiments should provide important new information conceding the effects of aging on stimulation-dependent protein phosphorylation in pre- and post-synaptic compartments of the rat hippocampus. Given the demonstrated link between protein phosphorylation and LTP and between LTP and aging, such information may provide new insights into the molecular and cellular bases of are-related changes in cognitive function.
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