TRANSCRIPTION FACTOR GENES, NEURONAL PLASTICITY, &AGING

The program of research outlined here 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 the neural plasticity
found in the rodent hippocampal formation, referred to as long-term
potentiation or enhancement (LTE), that may reflect processes normally
involved in information storage in the brain. Although a rather large
body of literature describes the phenomenological properties of LTE, and
there is a rather good understanding of LTE's requirements for induction,
there is as yet no clear understanding of the processes responsible for
its maintenance. Recent evidence suggests that certain of the
transcription factor genes (zif/268) can be rapidly activated by
LTE-inducing stimulation (Cole et al., 1989). These data suggest the
exciting possibility that transcription factor genes may regulate other
proteins that play a critical role in the maintenance of neural
plasticity in brain. Because the mechanisms of LTE induction appear to
be normal while the maintenance of LTE is deficient in aged rats (Barnes
and McNaughton, 1985), it is of interest to determine whether
transcription factor activation mechanisms are defective in old animals.
Because the rate of decay of LTE and spatial behavioral forgetting rates
are correlated within age groups, such investigations may provide
insights into why older organism show faster forgetting. Understanding
such changes in neuronal plasticity may have an impact on therapeutic
strategies for memory disorders in both normal and pathological conditions of aging. The experimental goals of the project can be broken into two main
aims: 1) Experiments to identify synaptic mechanisms that regulate
transcription factor genes in brain, and in the same preparation to
correlate transcription factor responses with synaptic enhancement (LTE).
Zif/268 mRNA and protein will be assayed by in situ hybridization and
immunohistochemistry, respectively, and will be correlated with the
degree of resultant plasticity. Additionally, we will examine the
responsiveness of other transcription factors. These studies will refine
our understanding of the relationship between LTE and transcription
factor activation and will form the basis for comparison of transcription
factor responses in young and old rats. 2) Experiments designed to
determine whether there are changes in regulation of transcription factor
activation in old animals that may contribute to their altered synaptic
plasticity and behavior. 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. has experience with chronic
electrophysiological techniques, and with behavior and physiology in
young and old rats; P.F.W. has experience with the anatomical and in
molecular techniques necessary to examine the transcription factors of
interest. We hope to combine our different techniques and apply the most
powerful available methods to test our hypotheses.