A Requirement for the Mitogen-activated Protein Kinase Cascade in Hippocampal Long Term Potentiation

Abstract

The mitogen-activated protein kinase (MAPK) cascade has been intensely studied as a primary biochemical pathway through which a variety of extracellular stimuli initiate and regulate processes of cellular transformation. That MAPKs are abundantly expressed in postmitotic neurons, however, suggests different yet currently unknown functions for this cascade in the mature nervous system. Here we report that the MAPK cascade is required for hippocampal long term potentiation (LTP), a robust and widely studied form of synaptic plasticity. We observed that PD 098059, a selective inhibitor of the MAPK cascade, blocked MAPK activation in response to direct stimulation of the NMDA receptor as well as to LTP-inducing stimuli. Furthermore, inhibition of the MAPK cascade markedly attenuated the induction of LTP. PD 098059, however, had no effect on the expression of established LTP, and the MAPK cascade was not persistently activated during LTP expression. Our observations provide the first demonstration of a role for the MAPK cascade in the activity-dependent modification of synaptic connections between neurons in the adult mammalian nervous system.The mitogen-activated protein kinase (MAPK) 1 cascade has been classically studied as a critical biochemical pathway involved in cellular transformation events such as cell proliferation and determination. Such work has delineated a pathway by which growth factor receptor activation initiates a complex cascade leading to the activation of Ras, Raf, and MEK, a dual-specific kinase that activates MAPKs via phosphorylations on both threonine and tyrosine residues (reviewed in Refs. 1 and 2).Although this cascade is typically studied in the context of mitotic cell regulation, its components are actually most abundantly expressed in postmitotic neurons of the developed nervous system (3, 4). At present, however, little is known about the physiologic roles of this cascade in mature neurons. We have begun to investigate the possible involvement of the MAPK cascade in the activity-dependent modulation of synaptic connections between neurons, a putative mechanism for the neuronal basis of learning and memory. In particular, we have examined the role of the MAPK cascade in hippocampal long term potentiation (LTP), a widely studied form of synaptic plasticity (reviewed in Refs. 5 and 6). Recently, we reported that p42 MAPK (extracellular signalregulated kinase 2) is activated during the induction of LTP in area CA1 of the hippocampus (7). Though this observation identifies the MAPK cascade as a potential component of the LTP induction cascades in area CA1, the physiologic necessity of MAPK activation during LTP induction remains to be established. To address this question, we have utilized the compound PD 098059 (8, 9), a recently described inhibitor of MEK, to block activation of the MAPK cascade during the delivery of LTP-inducing stimuli. Here we report that inhibition of the MAPK cascade greatly attenuates the induction but not expression of LTP in area CA1. Our observations provide ...

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