Activation of group III mGluRs inhibits GABAergic and glutamatergic transmission in the substantia nigra pars reticulata.
The GABAergic projection neurons of the substantia nigra pars reticulata (SNr) exert an important influence on the initiation and control of movement. The SNr is a primary output nucleus of the basal ganglia (BG) and is controlled by excitatory inputs from the subthalamic nucleus (STN) and inhibitory inputs from the striatum and globus pallidus. Changes in the output of the SNr are believed to be critically involved in the development of a variety of movement disorders. Anatomical studies reveal that metabotropic glutamate receptors (mGluRs) are highly expressed throughout the BG. Interestingly, mRNA for group III mGluRs are highly expressed in STN, striatum, and globus pallidus, and immunocytochemical studies have shown that the group III mGluR proteins are present in the SNr. Thus it is possible that group III mGluRs play a role in the modulation of synaptic transmission in this nucleus. We performed whole cell patch-clamp recordings from nondopaminergic SNr neurons to investigate the effect of group III mGluR activation on excitatory and inhibitory transmission in the SNr. We report that activation of group III mGluRs by the selective agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 100 microM) decreases inhibitory synaptic transmission in the SNr. Miniature inhibitory postsynaptic currents studies and paired-pulse studies reveal that this effect is mediated by a presynaptic mechanism. Furthermore we found that L-AP4 (500 microM) also reduces excitatory synaptic transmission at the STN-SNr synapse by action on presynaptically localized group III mGluRs. The finding that mGluRs modulate the major inputs to SNr neurons suggests that these receptors may play an important role in motor function and could provide new targets for the development of pharmacological treatments of movement disorders.
Wittmann
M
M
Department of Pharmacology, Emory University, Atlanta, Georgia 30322, USA.
Marino
M J
MJ
Bradley
S R
SR
Conn
P J
PJ
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000596:Amino Acids / Q000494:pharmacology; D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D015195:Drug Design; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects*; D018756:GABA Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010768:Phosphoserine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000187:drug effects* / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism*; D014966:Xanthenes / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D000596:Amino Acids; D000613:Aminobutyrates; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; C114624:LY 341495; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D017661:Receptors, Presynaptic; D014966:Xanthenes; C104331:cyclopropyl-4-phosphonophenylglycine; C102718:metabotropic glutamate receptor 3; D010768:Phosphoserine; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; C012729:2-amino-4-phosphonobutyric acid; D007608:Kainic Acid; D005998:Glycine; D001640:Bicuculline