A Role for ERK MAP Kinase in Physiologic Temporal Integration in Hippocampal Area CA1

Abstract

Recent studies demonstrate a requirement for the Extracellular signal Regulated Kinase (ERK) mitogen-activated protein kinase (MAPK) cascade in both the induction of long-lasting forms of hippocampal synaptic plasticity and in hippocampus-dependent associative and spatial learning. In the present studies, we investigated mechanisms by which ERK might contribute to synaptic plasticity at Schaffer collateral synapses in hippocampal slices. We found that long-term potentiation (LTP) induced with a pair of 100-Hz tetani does not require ERK activation in mice whereas it does in rats. However, in mice, inhibition of ERK activation blocked LTP induced by two LTP induction paradigms that mimicked the endogenous rhythm. In an additional series of studies, we found that mice specifically deficient in the ERK1 isoform of MAPK showed no impairments in tests of hippocampal physiology. To investigate ERK-dependent mechanisms operating during LTP-inducing stimulation paradigms, we monitored spike production in the cell body layer of the hippocampus during the period of -like LTP-inducing stimulation. -burst stimulation (TBS) produced a significant amount of postsynaptic spiking, and the likelihood of spike production increased progressively over the course of the three trains of TBS independent of any apparent increase in Excitatory Post-Synaptic Potential (EPSP) magnitude. Inhibition of ERK activation dampened this TBS-associated increase in spiking. These data indicate that, for specific patterns of stimulation, ERK may function in the regulation of neuronal excitability in hippocampal area CA1. Overall, our data indicate that the progressive increase in spiking observed during TBS represents a form of physiologic temporal integration that is dependent on ERK MAPK activity.Although evidence from studies of hippocampal synaptic plasticity and of the behaving animal indicates that activation of protein kinases contributes to the formation of memories, the underlying signal transduction mechanisms remain largely unknown. In particular, although a variety of studies with protein kinase inhibitors demonstrate a necessity for protein kinase activation in the induction of longterm potentiation (LTP) in hippocampal area CA1, the basis for kinase inhibitors blocking LTP induction is unclear. The pluripotent nature and structural diversity of most second messenger-regulated kinases make it difficult to determine precisely which downstream targets and physiologic effects are necessary components of kinase regulation of LTP induction.An increasing number of studies of late have investigated the role of the ERK mitogen-activated protein kinase (MAPK) cascade in hippocampal synaptic plasticity. Several laboratories have demonstrated that inhibitors of ERK MAPK activation, that is, inhibitors of the dedicated upstream regulator of ERK Mitogen and Extracellular signal regulated Kinase (MEK), block the induction of N-Methyl-D-Aspartate (NMDA) receptor-dependent LTP. In the present studies, we sought to begin to extend these studies by inves...

ERK activation in axonal varicosities modulates presynaptic plasticity in the CA3 region of the hippocampus through synapsin I

“…Another possibility is that LTP-inducing stimuli may produce lower levels of ERK activation in MF terminals of the rat hippocampal slices (7) compared with mouse. Indeed, substantial differences of ERK involvement in the molecular processes underlying LTP in these 2 species have been reported previously (3,43). Nonetheless, our results agree with previous data (7) in revealing that ERK, despite being activated by HFS, is not required for the induction and maintenance of MF-CA3 LTP for at least 1 h. Whether later effects of ERK signaling may be involved in the modifications underlying long-lasting plasticity at this pathway remains to be explored.…”

Domain Contributions to Signaling Specificity Differences Between Ras-Guanine Nucleotide Releasing Factor (Ras-GRF) 1 and Ras-GRF2

“…For TBS-LTP in the CA1 mediated by GRF2, ERK MAPK activation is known to be necessary, but not sufficient (10,14). Our data imply that the GRF2 CDC25 domain contributes to signaling specificity required for TBS-LTP induction because its ability to promote ERK MAPK activation is better than that of the same domain in GRF1.…”

“…ERK MAPK activity has also been shown to be necessary, but not sufficient, for TBS to induce LTP in the CA1 hippocampus (10,14). Moreover, ERK MAPK is a known downstream target of GRF2 through its CDC25 domain via activation of Ras proteins.…”

Modulation of Presynaptic Plasticity and Learning by the H-ras/Extracellular Signal-Regulated Kinase/Synapsin I Signaling Pathway

“…Using whole-cell patch clamp, LTP was reliably induced by 100 pairings at 0.5 Hz of a single presynaptic stimulus with a 200 ms postsynaptic current injection and train of action potentials (APs). The whole-cell patch-clamp configuration provided an additional opportunity to detect changes in postsynaptic plasticity because many previous studies have demonstrated that associative LTP requires intact postsynaptic ERK signaling (Watanabe et al, 2002;Zhu et al, 2002;Selcher et al, 2003). Therefore, we used potassium methyl-sulfate in the patch pipette solution to avoid blockade of A-type potassium channels that are modulated by postsynaptic ERK and regulate dendritic excitability (Yuan et al, 2002;Frick et al, 2004).…”