Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation

Abstract

RECENT studies in invertebrates indicate that a rapid genomic response to neuronal stimulation has a critical role in long-term changes in synaptic efficacy1. Because several of the genes (immedi-ately early genes; lEGs) that respond rapidly to growth factor stimulation of vertebrate cells in vitro 2-7 are also activated by neuronal stimulation in vivo 8-13, attention has focused on the possibility that they play a part in synaptic plasticity in vertebrate nervous systems. Four lEGs thought to encode transcription fac-tors, zif/268 5 (also termed Egr-l l4, NGFI-A 15, Krox24 16), C-fOS 17, c-jun 18, and jun-B 7 are rapidly induced in the brain by seizure activity8,11,13, and we have now studied the induction of these genes in a well-characterized model of synaptic plasticity in the verte-brate brain—-long-term potentiation (LTP) of the perforant path-granule cell (pp-gc) synapse in vivo 19. We found that high-frequency (but not low-frequency) stimulation of the pp-gc synapse markedly increases zif/268 messenger RNA (mRNA) levels in the ipsilateral granule cell neurons; mRNA of c-fos, c-jun and jun-B is less consistently increased. The stimulus frequency and intensity required to increase zif/268 mRNA levels are similar to those required to induce LTP, which is also seen only ipsilaterally, and both responses are blocked by NMDA-receptor antagonists as well as by convergent synaptic inhibitory inputs already known to block LTP20. Accordingly, zif/268 mRNA levels and LTP seem to be regulated by similar synaptic mechanisms.