Activation of Group I Metabotropic Glutamate Receptors Produces a Direct Excitation and Disinhibition of GABAergic Projection Neurons in the Substantia Nigra Pars Reticulata

Overview

Journal J Neurosci

Specialty Neurology

Date 2001 Sep 11

PMID 11549710

Citations 39

Authors

M J Marino

M Wittmann

S R Bradley

G W Hubert

Y Smith

P J Conn

Affiliations

Soon will be listed here.

Abstract

A pathological increase in excitatory glutamatergic input to substantia nigra pars reticulata (SNr) from the subthalamic nucleus (STN) is believed to play a key role in the pathophysiology of Parkinson's disease. We present an analysis of the physiological roles that group I metabotropic glutamate receptors (mGluRs) play in regulating SNr functions. Immunocytochemical analysis at the light and electron microscopic levels reveal that both mGuR1a and mGluR5 are localized postsynaptically in the SNr. Consistent with this, activation of group I mGluRs depolarizes SNr GABAergic neurons. Interestingly, although both group I mGluRs (mGluR1 and mGluR5) are expressed in these neurons, the effect is mediated solely by mGluR1. Light presynaptic staining for mGluR1a and mGluR5 was also observed in some terminals forming symmetric synapses and in small unmyelinated axons. Consistent with this, activation of presynaptic mGluR1a and mGluR5 decreases inhibitory transmission in the SNr. The combination of direct excitatory effects and disinhibition induced by activation of group I mGluRs could lead to a large excitation of SNr projection neurons. This suggests that group I mGluRs are likely to play an important role in the powerful excitatory control that the STN exerts on basal ganglia output neurons.

Citing Articles

The Neuroprotective Effects of mGlu1 Receptor Antagonists Are Mediated by an Enhancement of GABAergic Synaptic Transmission via a Presynaptic CB1 Receptor Mechanism.

Landucci E, Berlinguer-Palmini R, Baccini G, Boscia F, Gerace E, Mannaioni G Cells. 2022; 11(19).

PMID: 36230976 PMC: 9562021. DOI: 10.3390/cells11193015.

Moderate ethanol drinking is sufficient to alter Ventral Tegmental Area dopamine neurons activity via functional and structural remodeling of GABAergic transmission.

Ilari A, Curti L, Petrella M, Cannella N, La Rocca A, Ranieri G Neuropharmacology. 2021; 203:108883.

PMID: 34785165 PMC: 9301096. DOI: 10.1016/j.neuropharm.2021.108883.

The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain.

Gasiorowska A, Wydrych M, Drapich P, Zadrozny M, Steczkowska M, Niewiadomski W Front Aging Neurosci. 2021; 13:654931.

PMID: 34326765 PMC: 8315271. DOI: 10.3389/fnagi.2021.654931.

Group 1 Metabotropic Glutamate Receptors in Neurological and Psychiatric Diseases: Mechanisms and Prospective.

Su L, Wang N, Han J, Shen Y Neuroscientist. 2021; 28(5):453-468.

PMID: 34088252 PMC: 9449437. DOI: 10.1177/10738584211021018.

Opposing actions of CRF-R1 and CB1 receptors on VTA-GABAergic plasticity following chronic exposure to ethanol.

Harlan B, Becker H, Woodward J, Riegel A Neuropsychopharmacology. 2018; 43(10):2064-2074.

PMID: 29946104 PMC: 6098046. DOI: 10.1038/s41386-018-0106-9.

References

Kingston A, Ornstein P, Wright R, Johnson B, Mayne N, Burnett J . LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology. 1998; 37(1):1-12. DOI: 10.1016/s0028-3908(97)00191-3. View

Alger B, Pitler T, Wagner J, Martin L, Morishita W, Kirov S . Retrograde signalling in depolarization-induced suppression of inhibition in rat hippocampal CA1 cells. J Physiol. 1996; 496 ( Pt 1):197-209. PMC: 1160836. DOI: 10.1113/jphysiol.1996.sp021677. View

Litschig S, Gasparini F, Rueegg D, Stoehr N, Flor P, Vranesic I . CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Mol Pharmacol. 1999; 55(3):453-61. View

Gereau 4th R, Conn P . Roles of specific metabotropic glutamate receptor subtypes in regulation of hippocampal CA1 pyramidal cell excitability. J Neurophysiol. 1995; 74(1):122-9. DOI: 10.1152/jn.1995.74.1.122. View

Kearney J, Frey K, Albin R . Metabotropic glutamate agonist-induced rotation: a pharmacological, FOS immunohistochemical, and [14C]-2-deoxyglucose autoradiographic study. J Neurosci. 1997; 17(11):4415-25. PMC: 6573540. View

Monn J, Valli M, Massey S, Wright R, Salhoff C, Johnson B . Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and.... J Med Chem. 1997; 40(4):528-37. DOI: 10.1021/jm9606756. View

Bergman H, Wichmann T, Karmon B, DeLong M . The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism. J Neurophysiol. 1994; 72(2):507-20. DOI: 10.1152/jn.1994.72.2.507. View

Smith Y, Charara A, Hanson J, Paquet M, Levey A . GABA(B) and group I metabotropic glutamate receptors in the striatopallidal complex in primates. J Anat. 2000; 196 ( Pt 4):555-76. PMC: 1468097. DOI: 10.1046/j.1469-7580.2000.19640555.x. View

Lujan R, Roberts J, Shigemoto R, Ohishi H, Somogyi P . Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1 alpha, mGluR2 and mGluR5, relative to neurotransmitter release sites. J Chem Neuroanat. 1997; 13(4):219-41. DOI: 10.1016/s0891-0618(97)00051-3. View

10.

Pisani A, Calabresi P, Centonze D, Bernardi G . Enhancement of NMDA responses by group I metabotropic glutamate receptor activation in striatal neurones. Br J Pharmacol. 1997; 120(6):1007-14. PMC: 1564563. DOI: 10.1038/sj.bjp.0700999. View

11.

Doze V, Cohen G, Madison D . Calcium channel involvement in GABAB receptor-mediated inhibition of GABA release in area CA1 of the rat hippocampus. J Neurophysiol. 1995; 74(1):43-53. DOI: 10.1152/jn.1995.74.1.43. View

12.

Testa C, Standaert D, Landwehrmeyer G, Penney Jr J, Young A . Differential expression of mGluR5 metabotropic glutamate receptor mRNA by rat striatal neurons. J Comp Neurol. 1995; 354(2):241-52. DOI: 10.1002/cne.903540207. View

13.

KERNER J, Standaert D, Penney Jr J, Young A, Landwehrmeyer G . Expression of group one metabotropic glutamate receptor subunit mRNAs in neurochemically identified neurons in the rat neostriatum, neocortex, and hippocampus. Brain Res Mol Brain Res. 1997; 48(2):259-69. DOI: 10.1016/s0169-328x(97)00102-2. View

14.

Richards C, Shiroyama T, Kitai S . Electrophysiological and immunocytochemical characterization of GABA and dopamine neurons in the substantia nigra of the rat. Neuroscience. 1997; 80(2):545-57. DOI: 10.1016/s0306-4522(97)00093-6. View

15.

Mannaioni G, Attucci S, Missanelli A, Pellicciari R, Corradetti R, Moroni F . Biochemical and electrophysiological studies on (S)-(+)-2-(3'-carboxybicyclo(1.1.1)pentyl)-glycine (CBPG), a novel mGlu5 receptor agonist endowed with mGlu1 receptor antagonist activity. Neuropharmacology. 1999; 38(7):917-26. DOI: 10.1016/s0028-3908(99)00021-0. View

16.

Conn P, Pin J . Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol. 1997; 37:205-37. DOI: 10.1146/annurev.pharmtox.37.1.205. View

17.

Fiorillo C, Williams J . Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature. 1998; 394(6688):78-82. DOI: 10.1038/27919. View

18.

Wichmann T, DeLong M . Models of basal ganglia function and pathophysiology of movement disorders. Neurosurg Clin N Am. 1998; 9(2):223-36. View

19.

Smith Y, Charara A, Paquet M, Kieval J, Pare J, Hanson J . Ionotropic and metabotropic GABA and glutamate receptors in primate basal ganglia. J Chem Neuroanat. 2001; 22(1-2):13-42. DOI: 10.1016/s0891-0618(01)00098-9. View

20.

Scanziani M, Gahwiler B, Thompson S . Presynaptic inhibition of excitatory synaptic transmission by muscarinic and metabotropic glutamate receptor activation in the hippocampus: are Ca2+ channels involved?. Neuropharmacology. 1995; 34(11):1549-57. DOI: 10.1016/0028-3908(95)00119-q. View