Metabotropic glutamate receptor 1 activity generates persistent, N-methyl-d-aspartate receptor-dependent depression of hippocampal pyramidal cell excitability

Authors

  • J. P. Clement,

    1. Department of Anatomy, Wyeth Applied Neurophysiology Group, University of Bristol School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    2. Department of Anatomy, MRC Centre for Synaptic Plasticity, University of Bristol School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
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  • A. D. Randall,

    1. Department of Anatomy, Wyeth Applied Neurophysiology Group, University of Bristol School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
    2. Department of Anatomy, MRC Centre for Synaptic Plasticity, University of Bristol School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
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  • J. T. Brown

    1. Department of Anatomy, MRC Centre for Synaptic Plasticity, University of Bristol School of Medical Sciences, University Walk, Bristol BS8 1TD, UK
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Dr A. D. Randall and Dr J. T. Brown, 2MRC Centre for Synaptic Plasticity, as above.
E-mail: Jon.Brown@bristol.ac.uk, A.D.Randall@bristol.ac.uk

Abstract

Metabotropic glutamate receptors (mGluRs) are involved in many forms of neuronal plasticity. In the hippocampus, they have well-defined roles in long-lasting forms of both synaptic and intrinsic plasticity. Here, we describe a novel form of long-lasting intrinsic plasticity that we call (S)-3,5-dihydroxyphenylglycine (DHPG)-mediated long-term depression of excitability (DHPG-LDE), and which is generated following transient pharmacological activation of group I mGluRs. In extracellular recordings from hippocampal slices, DHPG-LDE was expressed as a long-lasting depression of antidromic compound action potentials (cAPs) in CA1 or CA3 cells following a 4-min exposure to the group I mGluR agonist (S)-DHPG. A similar phenomenon was also seen for orthodromic fibre volleys evoked in CA3 axons. In single-cell recordings from CA1 pyramids, DHPG-LDE was manifest as persistent failures in antidromic action potential generation. DHPG-LDE was blocked by (S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid (LY367385), an antagonist of mGluR1, but not 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), an mGluR5 inhibitor. Although insensitive to antagonists of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate/kainate and γ-aminobutyric acidA receptors, DHPG-LDE was blocked by antagonists of N-methyl-d-aspartate (NMDA) receptors. Similarly, in single-cell recordings, DHPG-mediated antidromic spike failures were eliminated by NMDA receptor antagonism. Long after (S)-DHPG washout, DHPG-LDE was reversed by mGluR1 antagonism. A 4-min application of (S)-DHPG also produced an NMDA receptor-dependent persistent depolarization of CA1 pyramidal cells. This depolarization was not solely responsible for DHPG-LDE, because a similar level of depolarization elicited by raising extracellular K+ increased the amplitude of the cAP. DHPG-LDE did not involve HCN channels or protein synthesis, but was eliminated by blockers of protein kinase C or tyrosine phosphatases.

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