Extracellular signal-regulated kinases (ERK1/2) have been implicated in the regulation of neuronal function and in the control of synaptic plasticity in the hippocampus. However, a precise knowledge of the cellular targets of ERK activation is still elusive. Recent evidences suggest that ERK, besides regulating gene expression in the neuron nucleus, may be activated in distinct subcellular compartments in response to different stimuli. We have previously shown that phosphorylated ERK1/2 (pERK) is localized at axospinous junctions of activated cortical neurons. To investigate the spatio-temporal dynamics of ERK activation in the hippocampus, we used confocal microscopic immunohistochemistry with a monoclonal antibody (Sigma) specific for pERK. Depolarization of hippocampal slices with a hyperkalemic solution (50 mM KCl) induced a strong increase of pERK immunoreactivity in the axon terminals of both mossy fibers in CA3 and Schaffer collaterals in CA1, which were identified by double labelling with an antibody against synapsin I (Chemicon). We next investigated whether long-term potentiation (LTP)-inducing stimuli recruit pERK at synaptic contacts. High-frequency stimulation (HFS) of the mossy fiber-CA3 pathway induced an increase of pERK immunoreactivity in mossy fiber nerve terminals. Presynaptic ERK activation showed a six-fold increase 5 minutes after the tetanus, returned to basal levels after 30 minutes and was completely blocked by the specific inhibitor U0126 (Promega). HFS of the Schaffer collateral-CA1 pathway resulted in a strong increase of pERK in the dendritic compartment of CA1 pyramidal neurons but not in presynaptic structures. These data show that LTP-inducing stimuli can activate ERK either in the pre- or in the post-synaptic compartment, a selective activation that is likely to reflect synapse-specific signalling. Thus, the spatial regulation of activated signaling cascades may represent a novel mechanism to achieve pathway and region-specific modification of synaptic strength. Support Contributed By: MIUR (FIRB, COFIN).
Pathway-specific induction of presynaptically activated ERKs in the hippocampus
PANZANELLI, Patrizia;BOGGIO, ELENA MARIA;SASSOE' POGNETTO, Marco;GIUSTETTO, Maurizio
2005-01-01
Abstract
Extracellular signal-regulated kinases (ERK1/2) have been implicated in the regulation of neuronal function and in the control of synaptic plasticity in the hippocampus. However, a precise knowledge of the cellular targets of ERK activation is still elusive. Recent evidences suggest that ERK, besides regulating gene expression in the neuron nucleus, may be activated in distinct subcellular compartments in response to different stimuli. We have previously shown that phosphorylated ERK1/2 (pERK) is localized at axospinous junctions of activated cortical neurons. To investigate the spatio-temporal dynamics of ERK activation in the hippocampus, we used confocal microscopic immunohistochemistry with a monoclonal antibody (Sigma) specific for pERK. Depolarization of hippocampal slices with a hyperkalemic solution (50 mM KCl) induced a strong increase of pERK immunoreactivity in the axon terminals of both mossy fibers in CA3 and Schaffer collaterals in CA1, which were identified by double labelling with an antibody against synapsin I (Chemicon). We next investigated whether long-term potentiation (LTP)-inducing stimuli recruit pERK at synaptic contacts. High-frequency stimulation (HFS) of the mossy fiber-CA3 pathway induced an increase of pERK immunoreactivity in mossy fiber nerve terminals. Presynaptic ERK activation showed a six-fold increase 5 minutes after the tetanus, returned to basal levels after 30 minutes and was completely blocked by the specific inhibitor U0126 (Promega). HFS of the Schaffer collateral-CA1 pathway resulted in a strong increase of pERK in the dendritic compartment of CA1 pyramidal neurons but not in presynaptic structures. These data show that LTP-inducing stimuli can activate ERK either in the pre- or in the post-synaptic compartment, a selective activation that is likely to reflect synapse-specific signalling. Thus, the spatial regulation of activated signaling cascades may represent a novel mechanism to achieve pathway and region-specific modification of synaptic strength. Support Contributed By: MIUR (FIRB, COFIN).
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