This program of research is directed towards an understanding of the mechanisms responsible for durable synaptic change in the mammalian central nervous system, and how these processes might be altered with age. The investigations focus on neural plasticity in rodent hippocampus, referred to as long-term potentiation or enhancement (LTP/LTE), that may reflect processes normally involved in information storage in the brain. Although there is good understanding of LTP's requirements for induction, there is as yet no clear understanding of the processes responsible for its maintenance. Recent evidence suggests that immediately early genes (IEGs) are rapidly activated by LTP- inducing stimulation (e.g., Cole et al., 1989), and raise the exciting possibility that specific IEGs play a critical role in the maintenance of neural plasticity in brain. The observations that LTP maintenance is reduced in aged rats, and that this reduction is correlated with behavioral deficits in spatial learning (Barnes and McNaughton, 1979), emphasizes the need to understand mechanisms that underlie the persistence of LTP, as such knowledge may contribute to selective therapeutic strategies for memory disorders in both normal and pathological conditions of aging. The experimental goals of the project are described by two principal aims:
AIM 1 - To examine cellular mechanisms that are rapidly induced by LTP stimulation and that may be involved in LTP maintenance;
AIM 2 - To determine whether the failure in old rats to maintain LTP and to exhibit deficits in spatial cognition can be explained, at least in part, by an alteration of signaling pathways involved in IEG expression. 1) Experiments in Aim 1 explore three different aspects of cell signaling that are likely to be involved in LTP maintenance. Experiment 1 will identify phosphoprotein signaling molecules that are rapidly phosphorylated following LTP. Experiment 2 will analyze a novel IEG that is induced in hippocampal granule cells by LTP stimulation. Experiment 3 will develop an in vivo technique to deliver antisense oligonucleotides to selectively block expression of IEGs and to assess the effect of this blockade on LTP maintenance. 2) Experiments in Aim 2 build upon the discovery made in the past grant period that the induction of the IEG c-fos , by a repetitive LTP stimulus, is selectively increased in aged, behaviorally- impaired rats. Experiment 4 examines whether there is an association between the memory ability of an individual rat and IEG mRNA induction. Experiment 5 examines the hypothesis that aging is associated with changes in LTP- induced signaling path- ways that lead to phosphorylation of specific proteins. Experiment 6 examines the hypothesis that the age-dependent reduction of LTP maintenance is associated with altered expression of specific IEG proteins. All studies proposed will use chronic in vivo electrophysiological methods that offer important advantages over acute or in vitro preparations for this work. The necessity for this collaboration is highlighted by the divergent expertise of the two principal investigators: C.A.B., chronic electrophysiological recording techniques and behavior in young and old rats; P.F.W., anatomical and molecular techniques necessary to examine the IEGs of interest. The strength of this interaction is the ability to combine and apply the most powerful available methods to test the hypotheses under study, which could not be accomplished in either laboratory in isolation.
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