Activation of mGluR1, PKC and MAP kinase pathway is required for postischemic LTP in the striatum

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Abstract

Excessive activation of glutamate receptors is widely accepted as one of the most important determinants in the development of the tissue damage produced by both cerebral ischemia and neurodegenerative disorders. However, how energy deprivation predisposes to excitotoxic insults is still largely unclear. To address this crucial issue, intracellular and whole-cell patch clamp recordings were performed from both striatal GABAergic projection neurons and cholinergic interneurons in a rat corticostriatal slice preparation. Interestingly, striatal GABAergic-projecting cells are highly vulnerable in the course of both brain ischemia and Huntington's disease, whereas striatal cholinergic interneurons tend to be spared by these insults, presumably reflecting a differential sensitivity to excitotoxic processes triggered by metabolic impairment. Accordingly, we found that brief periods (3-4 min) of combined oxygen and glucose deprivation causes in striatal projection neurons, but not cholinergic interneurons, a dramatic and irreversible increase in neuronal sensitivity to synaptically released glutamate (postischemic, long-term potentiation, i-LTP). This pathological form of synaptic plasticity is dependent on the stimulation of NMDA glutamate receptors but involves both NMDA- and AMPA-mediated synaptic transmission. Stimulation of metabotropic glutamate receptors 1 (mGluRs1) is a critical requirement for the induction of i-LTP since it is fully prevented by selective antagonists of this receptor subtype and is absent in mice lacking mGluRs1. Intracellular application of either calcium-chelating agents or protein kinase C (PKC) inhibitors blocks the induction of i-LTP, indicating that calcium elevation and PKC activation represent the postreceptor events leading to this pathological form of synaptic plasticity. Finally, the pharmacological inhibition of mitogen-activated protein (MAP) kinase ERK also prevents i-LTP, supporting the conclusion that ischemia- and glutamate-activated intracellular events converge on this downstream cellular effector to induce i-LTP. It is proposed that this synaptic phenomenon might be responsible for delayed neuronal death in several pathological conditions and that its pharmacological modulation might constitute an alternative approach to the therapy of both acute and chronic neurological disorders.

Original languageEnglish
JournalNeurological Sciences
Volume21
Issue number4 SUPPL.
Publication statusPublished - 2000

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

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