title: Activation of group II metabotropic glutamate receptors induces long-term depression of excitatory synaptic transmission in the substantia nigra pars reticulata.
abstract: Activation of group II metabotropic glutamate receptors (mGlu2 and mGlu3) has been implicated as a potential therapeutic strategy for treating both motor symptoms and progressive neurodegeneration in Parkinson's disease (PD). Modulation of excitatory transmission in the basal ganglia represents a possible mechanism by which group II mGlu agonists could exert antiparkinsonian effects. Previous studies have identified reversible effects of mGlu2/3 activation on excitatory transmission at various synapses in the basal ganglia, including the excitatory synapse between the subthalamic nucleus (STN) and the substantia nigra pars reticulata (SNr). Using whole-cell patch clamp studies of GABAergic SNr neurons in rat midbrain slices, we have found that a prolonged activation of group II mGlus by the selective agonist LY379268 induces a long-term depression (LTD) of evoked excitatory postsynaptic current (EPSC) amplitude. Bath application of LY379268 (100nM, 10min) induced a marked reduction in EPSC amplitude, and excitatory transmission remained depressed for at least 40min after agonist washout. The effect of LY379268 was concentration-dependent and was completely blocked by the group II mGlu-preferring antagonist LY341495 (500nM). To determine the relative contributions of mGlu2 and mGlu3 to the LTD induced by LY379268, we tested the ability of LY379268 (100nM) to induce LTD in wild type mice and mice lacking mGlu2 or mGlu3. LY379268 induced similar LTD in wild type mice and mGlu3 knockout mice, whereas LTD was absent in mGlu2 knockout mice, indicating that mGlu2 activation is necessary for the induction of LTD in the SNr. These studies suggest a novel role for mGlu2 in the long-term regulation of excitatory transmission in the SNr and invite further exploration of mGlu2 as a therapeutic target for treating the motor symptoms of PD.
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Kari A
authors.initials: KA
authors.lastname: Johnson
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Niswender
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: zixiu.xiang@vanderbilt.edu.
authors.forename: Zixiu
authors.initials: Z
authors.lastname: Xiang
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000502:physiology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects*; D014966:Xanthenes / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D005680:gamma-Aminobutyric Acid