Metabotropic glutamate receptor 1 activity generates persistent, N-methyl-D-aspartate receptor-dependent depression of hippocampal pyramidal cell excitability.
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 alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate/kainate and gamma-aminobutyric acid(A) 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.
Clement
J P
JP
Department of Anatomy, Wyeth Applied Neurophysiology Group, University of Bristol School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.
Randall
A D
AD
Brown
J T
JT
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C104077:metabotropic glutamate receptor type 1; D011188:Potassium