THRESHOLDS FOR SYNAPTIC ACTIVATION OF TRANSCRIPTION FACTORS IN HIPPOCAMPUS - CORRELATION WITH LONG-TERM ENHANCEMENT

Recent studies suggest a role for rapid induction of transcription fac tors in stimulus-induced neuronal plasticity in the mammalian brain. S ynaptic activation of transcription factors has been analyzed in the h ippocampus using the long-term potentiation or enhancement (LTP/LTE) p aradigm. Using this approach, several studies have identified transcri ption factors that are induced in hippocampal granule cells by NMDA re ceptor-dependent mechanisms; however, the link between long-term plast icity and activation of these genes has been called into question by r eports suggesting that the thresholds for LTE and gene activation diff er. To address this issue, we have used a chronic in vivo recording te chnique to monitor mRNA responses of several transcription factor gene s to two different patterns of LTE-inducing electrical stimulation of entorhinal cortical afferents to hippocampus. One pattern consisted of 10 repetitions of a 20 or 25 msec train of pulses at 400 Hz (80 or 1 00 pulses total). This ''10-train'' pattern has been used in previous studies of LTE and produces robust synaptic enhancement lasting at lea st 3 d (Barnes, 1979). The other stimulation pattern consisted of 50 r epetitions of a 20 msec train delivered at 400 Hz (400 pulses total), which is similar to parameters used in other studies reporting inducti on of c-fos in association with LTE (Dragunow et al., 1989; Jeffery et al., 1990; Abraham et al., 1992). Our results indicate that expressio n of zif268, monitored by in situ hybridization and immunostaining, is strongly induced by the 10-train stimulus pattern to levels similar t o those induced by seizure activity. JunB mRNA levels are also modestl y increased by the 10-train stimulus pattern; however, increases in Ju nB immunostaining were not detected. Neither c-fos nor c-jun mRNA were detectably induced by this-stimulus. In contrast, the 50-train stimul us pattern resulted in a robust induction of c-fos and c-jun mRNA, in addition to zif268 and junB. Transcription factor responses to either stimulus pattern were blocked by the noncompetitive NMDA receptor anta gonist MK-801. Identical transcription factor responses were observed in adult (6-12-month-old) and aged (23-26-month-old) rats, suggesting that synaptic mechanisms involved in these responses are preserved in aged animals. Analysis of LTE following either the 10- or 50-train sti mulus patterns revealed identical magnitudes of initial induction and decay kinetics (approximately 3 d) and indicates that the 1 0-train st imulus pattern is sufficient to produce maximal synaptic enhancement. These studies define distinct thresholds for NMDA-dependent induction of transcription factors in hippocampus and indicate that, of the tran scription factor genes examined, only the threshold for activation of zif268 is similar to that for LTE.