Mitogen-activated protein kinases in synaptic plasticity and memory

Abstract

This review highlights five areas of recent discovery concerning the role of extracellular-signal regulated kinases (ERKs) in the hippocampus. First, ERKs have recently been directly implicated in human learning through studies of a human mental retardation syndrome. Second, new models are being formulated for how ERKs contribute to molecular information processing in dendrites. Third, a role of ERKs in stabilizing structural changes in dendritic spines has been defined. Fourth, a crucial role for ERKs in regulating local dendritic protein synthesis is emerging. Fifth, the importance of ERK interactions with scaffolding and structural proteins at the synapse is increasingly apparent. These topics are discussed within the context of an emerging role for ERKs in a wide variety of forms of synaptic plasticity and memory formation in the behaving animal.

Introduction

Signal transduction mechanisms are integral components of the neuronal information processing machinery. Signaling through cellular protein kinase cascades impinges upon targets at the neuronal membrane, in the cytoplasm, and within the nucleus in order to effect changes in synaptic function and connectivity.

In this review I focus on the role of signal transduction mechanisms in synaptic plasticity and memory formation. By-and-large I discuss the involvement of these processes in hippocampal function because the hippocampus is involved in the highest-order forms of memory: declarative, episodic, and spatial memory. These higher-order aspects of memory function in cognition are the processes many of us are most interested in ultimately understanding. An additional reason to focus on the hippocampus is that there are behavioral assays to assess hippocampus-dependent learning and memory in rodents, which combined with the phenomenal recent progress in genetic engineering techniques has allowed for amazing progress in understanding the molecular basis of hippocampus-dependent cognitive processing. Equally as importantly, the rodent hippocampal slice preparation allows the study of use-dependent, long-lasting forms of synaptic plasticity such as long-term potentiation (LTP), which provides us with an in vitro system for studying the role of signal transduction mechanisms in the context of lasting alterations of synaptic function.

Progress in this area during the past few years has revealed some surprises about the role of signal transduction mechanisms in hippocampal synaptic plasticity and memory formation. First and foremost is the extraordinary complexity of biochemical signaling that is involved in triggering LTP and the formation of long-term memories [1]. Numerous signaling systems including the cAMP cascade, calcium/calmodulin dependent kinases, nitric oxide/cGMP/cyclic GMP-dependent protein kinase (PKG), protein kinase C (PKC), redox modulation, growth factor receptor tyrosine kinases, rho/rac signaling, cell adhesion molecules, and the mitogen-activated protein kinases (MAPKs) all have been implicated as playing crucial parts in hippocampal synaptic plasticity and hippocampus-dependent memory formation. Moreover, it is now clear that there is substantial interplay between and among these signaling pathways, increasing the level of complexity and implying a great degree of integration and coordination for signal transduction in hippocampal LTP induction. Although this degree of complexity was unanticipated 20 years ago, it now appears that complexity of cellular signaling could be the rule rather than the exception for plasticity at both adult and developing synapses. In retrospect, this is perhaps not surprising because signal transduction cascades are in essence biochemical information processing systems, and great sophistication at this level is necessary for neurons and synapses to appropriately compute whether or not to trigger a long-lasting change in their function.

Against this backdrop, for a short review such as this it is necessary to focus on only a few specific aspects of signal transduction mechanisms in plasticity and memory. For this review I have chosen to focus on the extracellular-signal regulated kinase (ERK) subfamily of MAPKs. In part I chose this cascade because of its novelty in the context of central nervous system (CNS) function — until recently the cascade had largely been investigated for its role in regulating cell division and differentiation in cells outside the CNS. I am also motivated to focus on ERK because a wide variety of recent studies during the past ten years indicate its clear importance in synaptic plasticity and memory formation in general, across many species, brain areas, and types of synapses (see 2., 3., 4., 5., 6., 7., 8., 9., 10., 11., 12., 13., 14.•, 15.•, 16. for some important recent examples and possible exceptions to this generalization). Finally, very exciting recent data have directly implicated dysregulation of ERK as a mechanism for a learning disorder in humans; neurofibromatosis-1 associated mental retardation.

The format of the review is as follows. In the first section I highlight what I consider to be two particularly exciting recent developments in the area of ERK function in plasticity and cognition. Space limitations do not allow me to give just treatment to these topics, but at least I am able to draw these areas to your attention, and hopefully prompt further reading of the primary literature. In the second section I speculate briefly on what I consider to be areas of future investigation ripe for discovery. Ideally this will prompt young investigators interested in this area to pursue these topics for their research projects. Regardless, those investigators (young and old) working on the five ‘hot topics’ discussed in this review might take some pleasure from the fact that their work is making considerable impact (see Figure 1, Figure 2).