Extracellular Signal-Regulated Protein Kinase Activation Is Required for Metabotropic Glutamate Receptor-Dependent Long-Term Depression in Hippocampal Area CA1

Abstract

Activation of group 1 metabotropic glutamate receptors (mGluRs) induces long-term depression (LTD) of synaptic transmission that relies on dendritic protein synthesis. We investigated the signal transduction pathways required for mGluR-LTD to identify candidate mechanisms for mGluR regulation of synaptic protein synthesis. Our results demonstrate a role for extracellular signal-regulated protein kinase (ERK), a subclass of the mitogen-activated protein kinases (MAPKs), in mGluR-LTD in area CA1 of the rat hippocampus. Inhibitors of the upstream kinase of ERK, MAP/ERK kinase significantly reduce mGluR-LTD induced by the group 1 agonist dihydroxyphenylglycine (DHPG) and synaptic stimulation but do not affect NMDA receptor-dependent LTD. In contrast, inhibitors of p38 MAPK were ineffective against DHPG-induced LTD. Consistent with the role of ERK in mGluR-LTD, we observed that DHPG treatment of hippocampal slices (isolated CA1), at concentrations that induce LTD, results in a robust phosphorylation of ERK but not of p38 MAPK. These results point to ERK as an important regulator of mGluR-LTD and a potential mechanism for mGluR regulation of synaptic protein synthesis.

Alteration of synaptic plasticity in rat dorsal striatum induced by chronic ethanol intake and withdrawal via ERK pathway

“…Although it has been previously shown that ERK phosphorylation is required for both LTP [9,10] and LTD [26,11] in hippocampal CA1 as well as LTD in the cerebellum [8] and LTP in other cortical areas [12] , we provide the first evidence that ERK activation is required for striatal LTD induction.…”

“…For example, stimuli inducing LTP in area CA1 of the hippocampus potently activate ERK [8] , whereas pharmacological inhibition of MEK, an upstream activator of ERK, inhibits LTP [8,9] . The participation of ERK in synaptic plasticity has also been found in other brain regions [10,11,12] (eg, LTD in the cerebellum and LTP in the visual cortex).…”

Leptin regulation of hippocampal synaptic function in health and disease

“…By contrast, however, an ERK-dependent cascade is implicated in leptin-induced LTD, as selective inhibitors of ERK activation block leptin action at P5-8 [29]. The role of ERK in leptin-induced LTD displays similarities to mGluR-dependent LTD, as activation of ERK is necessary for endocytosis of AMPA receptors and LTD [51]. Thus, although AMPA receptor internalization may be common to both leptin-induced LTD at P5-8 and LFS-induced LTD, it is likely that divergent signalling pathways promote AMPA receptor removal from synapses.…”

p38 Mitogen-Activated Protein Kinase Contributes to Adenosine A1Receptor-Mediated Synaptic Depression in Area CA1 of the Rat Hippocampus

“…The ERK 1/2 MAPK pathway is also required for metabotropic glutamate receptor-dependent long-term depression (Gallagher et al, 2004). We tested whether ERK 1/2 MAPK also played a role in adenosine-mediated synaptic depression.…”