title: Presynaptic group II metabotropic glutamate receptors reduce stimulated and spontaneous transmitter release in human dentate gyrus.
abstract: Metabotropic glutamate receptors (mGluRs) control excitatory neurotransmission as inhibitory autoreceptors at many synapses throughout the CNS. Since pharmacological activation of mGluRs potently depresses excitatory transmission, anticonvulsive effects were found in a number of experimental epilepsies. However, although native rodent mGluRs and heterologously expressed human mGluRs have so far been investigated in great detail, our knowledge about native human mGluRs in situ is limited. Here we used acute human hippocampal slices prepared from hippocampi surgically removed for the treatment of temporal lobe epilepsy in order to investigate the modulation of glutamatergic transmission by human mGluRs at the perforant path-granule cell synapse. The broad spectrum mGluR agonist (1S, 3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) profoundly and reversibly reduced field EPSPs (fEPSPs) with an EC(50) of 30+/-7.4 microM. Paired-pulse depression of fEPSPs was converted into strong facilitation. The inhibition of fEPSPs by ACPD was mimicked by the specific group II mGluR agonist (2S, 2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV), while the specific group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) was ineffective. The effect of ACPD was blocked by group II antagonist (2S,3S,4S)-2methyl-2-(carboxycyclopropyl)glycine (MCCG) but was not changed by coapplication of the specific group III antagonist (S)2 amino2methyl4phosphonobutanoic acid (MAP4). ACPD reduced pharmacologically isolated intracellular EPSPs in granule cells to the same extent as fEPSPs, whereas a specific group III agonist had no effect on EPSPs. Whole-cell recordings from morphologically identified granule cells revealed that DCG-IV significantly reduced the frequency of miniature EPSCs (mEPSCs) in granule cells while the mean amplitude of mEPSCs was not affected. We conclude that in human dentate gyrus mGluR2/3 can almost completely depress glutamate release by a presynaptic mechanism which acts downstream of presynaptic voltage gated calcium-entry and most likely involves a direct modulation of the release machinery.
authors.affiliation: Experimental Neurophysiology, Department of Neurosurgery, University Clinic Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. dirk.dietrich@ukb.uni-bonn.de
authors.forename: D
authors.initials: D
authors.lastname: Dietrich
authors.forename: T
authors.initials: T
authors.lastname: Kral
authors.forename: H
authors.initials: H
authors.lastname: Clusmann
authors.forename: M
authors.initials: M
authors.lastname: Friedl
authors.forename: J
authors.initials: J
authors.lastname: Schramm
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000998:Antiviral Agents / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism*; D004148:Dioxolanes / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000502:physiology*; D013268:Stimulation, Chemical
chemical_list: D000998:Antiviral Agents; D004148:Dioxolanes; D018377:Neurotransmitter Agents; D011687:Purines; D018094:Receptors, Metabotropic Glutamate; D017661:Receptors, Presynaptic; C108822:metabotropic glutamate receptor 2; C104068:4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolane-2-methanol; D018698:Glutamic Acid