The formation of long-term memory is thought to depend on long-lasting changes in synaptic efficacy and the reorganisation of neuronal networks. Experimental evidence suggests that the mechanisms underlying these processes engage the genetic program of neurons and de novo synthesis of proteins. To date, the prevailing model for cellular consolidation underlying the laying down of memory suggests that synapse-to-nuclear signalling and transcriptional regulation of genes are required to maintain long-lasting synaptic modification in neural networks activated during learning. Although the molecular events coupling cell activation to gene transcription have not been entirely resolved, two important steps in this process appear to be critical: the activation of protein kinases and of constitutively expressed transcription factors and, shortly after, the expression of a class of inducible immediate early genes (IEGs) encoding regulatory transcription factors that interact with promoter regulatory elements of a host of downstream effector genes. Zif268, also known as Krox24, Egr1 or NGFI-A, is one such IEG encoding a zinc finger transcription factor of the Egr family, which has been implicated in synaptic plasticity and memory consolidation.

Here, we first describe experiments showing that the ERK family of mitogen-activated protein kinase (MAPK) is critically involved in LTP-induced regulation of zif268 in vivo. In these experiments, we found that LTP in the dentate gyrus leads to rapid phosphorylation of MAPK/ERK and subsequent co-ordinated phosphorylation of the two downstream transcription factors, CREB and Elk-1. Inhibition of MAPK/ERK phosphorylation by a MEK inhibitor was shown to block phosphorylation of both CREB and Elk-1, and also to block LTP-dependent transcriptional activation of zif268 in dentate granule cells, resulting in a rapidly decaying LTP. These results show that MAPK/ERK controls zif268 expression in LTP and that this is mediated by two parallel and possibly co-operating signalling pathways, one targeting CRE-mediated transcription via CREB and the second targeting SRE-mediated transcription via Elk-1 (Davis et al. 2000). Next, in collaboration with Tim Bliss and his colleagues we investigated the role of zif268 in LTP and learning using mutant mice in which the zif268 gene is inactivated (Jones et al. 2001). In these mice, basal synaptic transmission and forms of short-term plasticity were normal in the dentate gyrus; however, LTP, which was normal for the first hour, was not maintained over 24 h in awake zif268 mutant mice, showing that the zif268 gene is necessary for the expression of the late phases of LTP. At the behavioural level, we found that long-term memory in zif268 mutant mice, but not short-term memory, is severely impaired in several tasks including social transmission of food preference, conditioned taste aversion and spatial navigation in the water-maze. We then explored the role of MAPK/ERK, CREB and zif268 in recognition memory, using a task based on the spontaneous preference of rodents for novelty and their ability to remember previously encountered objects. Our results show that blocking MAPK/ERK activation by inhibiting the upstream kinase MEK, turning CREB function off in transgenic mice, or inactivating zif268 in mutant mice, all resulted in a similar deficit in long-term, but not short-term, recognition memory (Bozon et al. 2003). Finally, we will describe experiments showing that this signalling cascade is also required for reconsolidation of recognition memory after retrieval (Kelly et al. 2003). Together with a wealth of experimental data showing that each of these molecules plays important roles in mediating long-term changes in neuronal function, our results are consistent with the view that MAPK/ERK activation and the subsequent transcriptional regulation of the IEG zif268 is an important signalling cascade recruited during, and required for, the formation of long-term memory.