Metabotropic glutamate receptors mGluR2 and mGluR5 are expressed in two non-overlapping populations of Golgi cells in the rat cerebellum

doi:10.1016/0306-4522(96)00316-8

Neuroscience

Volume 75, Issue 3, December 1996, Pages 815-826

https://doi.org/10.1016/0306-4522(96)00316-8 Get rights and content

Abstract

The metabotropic glutamate receptor subtypes mG1uR2 and mG1uR5, which are thought to be coupled respectively to the inhibitory cyclic adenosine monophosphate (cAMP) cascade and the phosphatidylinositol hydrolysis/Ca²⁺ cascade, are known to be expressed on Golgi cells in the granular layer of the rat cerebellar cortex. In the present immunohistochemical study with a monoclonal antibody against mG1uR2 and a polyclonal antibody for mG1uR5, we examined whether or not mG1uR2- and mGluR5-like immunoreactivities were both present in single Golgi cells in the rat cerebellar cortex. In double immunofluorescence histochemistry, no Golgi cells showed mG1uR2- and mG1uR5-like immunoreactivities simultaneously. Of the total number of Golgi cells immunoreactive for mG1uR2 or mG1uR5, about 90% were mG1uR2-like immunoreactive, and about 10% were mG1uR5-like immunoreactive. Golgi cells with mG1uR2-like immunoreactivity were distributed evenly in the granular layer of all the cerebellar regions, while those with mG1uR5-like immunoreactivity were distributed more frequently in the 1, II, VII–X lobules of the vermis and the copula pyramidis of the hemisphere than in other cerebellar regions.

The results indicate that Golgi cells containing mG1uR2 are segregated from those possessing mG1uR5. These two populations of Golgi cells, each equipped with a different metabolic glutamate receptor coupled to a different intracellular signal transduction system, may play different roles in the glutamatergic neuronal circuits in the cerebellar cortex.

References (32)

AbeT. et al.
Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca²⁺ signal transduction
J. biol. Chem.
(1992)
AokiE. et al.
New candidates for GABAergic neurons in the rat cerebellum: an immunocytochemical study with anti-GABA antibody
Neurosci. Lett.
(1986)
BraakE. et al.
The new monodendritic neuronal type within the adult human cerebellar granule cell layer shows calretinin-immunoreactivity
Neurosci. Lett.
(1993)
CozziM.G. et al.
Immunohistochemical localization of secretogranin II in the rat cerebellum
Neuroscience
(1989)
FoxC.A. et al.
The primate cerebellar cortex: A Golgi and electron microscopic study. In The Cerebellum
IllingR.B.
A subtype of cerebellar Golgi cells may be cholinergic
Brain Res.
(1990)
MunozD.G.
Monodendritic neurons: a cell type in the human cerebellar cortex identified by chromogranin A-like immunoreactivity
Brain Res.
(1990)
NakanishiS.
Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity
Neuron
(1994)
NekiA. et al.
Pre- and postsynaptic localization of a metabotropic glutamate receptor, mG1uR2, in the rat brain. An Immunohistochemical study with a monoclonal antibody
Neurosci. Lett.
(1996)
OhishiH. et al.
Immunohistochemical localization of metabotropic glutamate receptors, mG1uR2 and mG1uR3, in rat cerebellar cortex
Neuron
(1994)

OhishiH. et al.

Distribution of the messenger RNA for a metabotropic glutamate receptor, mG1uR2, in the central nervous system of the rat

Neuroscience

(1993)

OttersenO.P. et al.

Colocalization of glycine-like and GABA-like immunoreactivities in Golgi cell terminals in the rat cerebellum: a postembedding light and electron microscopic study

Brain Res.

(1988)

PinJ.P. et al.

The metabotropic glutamate receptors: structure and functions

Neuropharmacology

(1995)

ShigemotoR. et al.

Immunohistochemical localization of a metabotropic glutamate receptor, mGluR5, in the rat brain

Neurosci. Lett.

(1993)

TanabeY. et al.

A family of metabotropic glutamate receptors

Neuron

(1992)

WilkinG.P. et al.

Localization of high affinity(³H)glycine transport sites in the cerebellar cortex

Brain Res.

(1981)

Cited by (85)

Membrane trafficking and positioning of mGluRs at presynaptic and postsynaptic sites of excitatory synapses
2021, Neuropharmacology
The plethora of functions of glutamate in the brain are mediated by the complementary actions of ionotropic and metabotropic glutamate receptors (mGluRs). The ionotropic glutamate receptors carry most of the fast excitatory transmission, while mGluRs modulate transmission on longer timescales by triggering multiple intracellular signaling pathways. As such, mGluRs mediate critical aspects of synaptic transmission and plasticity. Interestingly, at synapses, mGluRs operate at both sides of the cleft, and thus bidirectionally exert the effects of glutamate. At postsynaptic sites, group I mGluRs act to modulate excitability and plasticity. At presynaptic sites, group II and III mGluRs act as auto-receptors, modulating release properties in an activity-dependent manner. Thus, synaptic mGluRs are essential signal integrators that functionally couple presynaptic and postsynaptic mechanisms of transmission and plasticity. Understanding how these receptors reach the membrane and are positioned relative to the presynaptic glutamate release site are therefore important aspects of synapse biology. In this review, we will discuss the currently known mechanisms underlying the trafficking and positioning of mGluRs at and around synapses, and how these mechanisms contribute to synaptic functioning. We will highlight outstanding questions and present an outlook on how recent technological developments will move this exciting research field forward.
This article is part of the Neuropharmacology Special Issue on ‘Glutamate Receptors – mGluRs’.
Cerebellar perineuronal nets in cocaine-induced pavlovian memory: Site matters
2017, Neuropharmacology
One of the key mechanisms for the stabilization of synaptic changes near the end of critical periods for experience-dependent plasticity is the formation of specific lattice extracellular matrix structures called perineuronal nets (PNNs). The formation of drug memories depends on local circuits in the cerebellum, but it is unclear to what extent it may also relate to changes in their PNN. Here, we investigated changes in the PNNs of the cerebellum following cocaine-induced preference conditioning. The formation of cocaine-related preference memories increased expression of PNN-related proteins surrounding Golgi inhibitory interneurons as well as that of cFos in granule cells at the apex of the cerebellar cortex. In contrast, the expression of PNNs surrounding projection neurons in the medial deep cerebellar nucleus (DCN) was reduced in all cocaine-treated groups, independently of whether animals expressed a preference for cocaine-related cues. Discriminant function analysis confirmed that stronger PNNs in Golgi neurons and higher cFos levels in granule cells of the apex might be considered as the cerebellar hallmarks of cocaine-induced preference conditioning. Blocking the output of cerebellar granule cells in α6Cre-Cacna1a mutant mice prevented re-acquisition, but not acquisition, of cocaine-induced preference conditioning. Interestingly, this impairment in consolidation was selectively accompanied by a reduction in the expression of PNN proteins around Golgi cells. Our data suggest that PNNs surrounding Golgi interneurons play a role in consolidating drug-related memories.
Expression of the K<sup>+</sup>/Cl<sup>−</sup> cotransporter, KCC2, in cerebellar Purkinje cells is regulated by group-I metabotropic glutamate receptors
2017, Neuropharmacology
Citation Excerpt :
mGlu1 receptors are abundantly expressed in dendrites of cerebellar Purkinje cells, and their activation is required for the induction of long-term depression of excitatory synaptic transmission at parallel fibre-Purkinje cell synapses and motor learning (Aiba et al., 1994; Conquet et al., 1994; Ichise et al., 2000; Hansel and Linden, 2000; Ohtani et al., 2014). mGlu5 receptors show low expression levels in the adult cerebellum, where they are mainly localized in Lugaro and Golgi cells (Neki et al., 1996; Négyessy et al., 1997). In the molecular layer, a small fraction of neurons are stained with mGlu5 receptor antibodies, and mGlu5 receptors are found in postsynaptic elements innervated by parallel fibres (Négyessy et al., 1997).
The neuronal K⁺/Cl⁻ symporter, KCC2, shapes synaptic responses mediated by Cl⁻-permeant GABA_A receptors. Moving from the evidence that excitatory neurotransmission drives changes in KCC2 expression in cerebellar neurons, we studied the regulation of KCC2 expression by group-I metabotropic glutamate (mGlu) receptors in the cerebellum of adult mice. Mice lacking mGlu5 receptors showed a large reduction in cerebellar KCC2 protein levels and a loss of KCC2 immunoreactivity in Purkinje cells. Similar changes were seen in mice treated with the mGlu5 receptor antagonist, MPEP, whereas treatment with the mGlu5 receptor positive allosteric modulator (PAM), VU0360172, increased KCC2 expression. In contrast, pharmacological inhibition of mGlu1 receptors with JNJ16259685 enhanced cerebellar KCC2 protein levels and KCC2 immunoreactivity in Purkinje cells, whereas treatment with the mGlu1 receptor PAM, RO0711401, reduced KCC2 expression. To examine whether the reduction in KCC2 expression caused by the absence or the inhibition of mGlu5 receptors could affect GABAergic transmission, we performed electrophysiological and behavioral studies. Recording of extracellular action potentials in Purkinje cells showed that the inhibitory effect of the GABA_A receptor agonist, muscimol, was lost in cerebellar slices prepared from mGlu5^−/− mice or from mice treated systemically with MPEP, in line with the reduction in KCC2 expression. Similarly, motor impairment caused by the GABA_A receptor PAM, diazepam, was attenuated in mice pre-treated with MPEP. These findings disclose a novel function of mGlu5 receptors in the cerebellum and suggest that mGlu5 receptor ligands might influence GABAergic transmission in the cerebellum and affect motor responses to GABA-mimetic drugs.
This article is part of the Special Issue entitled ‘Metabotropic Glutamate Receptors, 5 years on’.
Developmental expression of mGlu2 and mGlu3 in the mouse brain
2016, Gene Expression Patterns
The glutamatergic system directs central nervous system (CNS) neuronal activity and may underlie various neuropsychiatric disorders. Glutamate transmits its effects through multiple receptor classes. Class II metabotropic glutamate receptors, mGlu2 and mGlu3, play an important role in regulating synaptic release of different neurotransmitter systems and consequently modulate signaling across several neuronal subtypes. Drugs targeting mGlu2 and mGlu3 are seen as potential therapeutics for various psychiatric and neurological disorders, and defining their expression through development can aid in understanding their distinct function.
Here, non-radioactive in situ hybridization was used to detect mGlu2 and mGlu3 mRNA in the CNS of 129SvEv mice at PN1, PN8, PN25, PN40, and PN100. At PN1, mGlu2 and mGlu3 are strongly expressed cortically, most notably in layer III and V. Subcortically, mGlu2 is detected in thalamic nuclei; mGlu3 is highly expressed in the striatum. By PN8, the most notable changes are in hippocampus and cortex, with mGlu2 densely expressed in the dentate gyrus, and showing increased cortical levels especially in medial cortex. At PN8, mGlu3 is observed in cortex and striatum, with highest levels detected in reticular thalamic nucleus. At PN25 patterns of expression approximated those observed across adulthood (PN40 & PN100): mGlu2 expression was high in cortex and dentate gyrus while mGlu3 showed expression in the reticular thalamic nucleus, cortex, and striatum. These studies provide a foundation for future research seeking to parse out the roles of mGlu2 from mGlu3, paving the way for better understanding of how these receptors regulate activity in the brain.
Lower [3H]LY341495 binding to mGlu2/3 receptors in the anterior cingulate of subjects with major depressive disorder but not bipolar disorder or schizophrenia
2016, Journal of Affective Disorders
Citation Excerpt :
Class II couple to Gi/o, negatively regulating activity of adenyl cyclase, as do Class III receptors (for review see (Ferraguti and Shigemoto, 2006)). Glutamate receptors have broad and overlapping expression patterns within the brain and, in this way, exert influential control over neural and neuronal activity (Neki et al., 1996a, 1996b; Ohishi et al., 1998) reviewed in (Ferraguti and Shigemoto, 2006). Dysregulation of the glutamatergic system has been widely implicated in psychiatric disease (Ouellet-Plamondon and Tony, 2012).
The glutamatergic system has recently been implicated in the pathogenesis and treatment of major depressive disorders(MDD) and mGlu2/3 receptors play an important role in regulating glutamatergic tone. We therefore measured cortical levels of mGlu2/3 to determine if they were changed in MDD.
Binding parameters for [³H]LY341495 (mGlu2/3 antagonist) were determined to allow optimized in situ binding with autoradiography to be completed using a number of CNS regions. Subsequently, density of [³H]LY341495 binding was measured in BA24(anterior cingulate cortex), BA17(visual cortex) and BA46(dorsolateral prefrontal cortex) from subjects with MDD, Bipolar Disorder(BPD), Schizophrenia(SCZ), and controls, as well as rats treated with imipramine (20 mg/kg), fluoxetine (10 mg/kg), or vehicle.
mGlu2/3 are widely expressed throughout the brain with high levels observed in cortex. [³H]LY341495 binding was significantly lower in BA24 from subjects with MDD (mean±SEM=141.3±14.65 fmol/ETE) relative to controls (184.9±7.76 fmol/ETE; Cohen’s d=1.005, p<0.05). There were no other differences with diagnoses, and chronic antidepressant treatment in rats had minimal effect on binding.
Using this approach we are unable to determine whether the change represents fluctuations in mGlu2, mGlu3, or both. Moreover, using postmortem tissue we are unable to dissociate the irrevocable confound of suicidality upon binding levels.
We have demonstrated lower [³H]LY341495 binding levels in MDD in BA24-a brain region implicated in depression. Moreover we show that the lower levels are unlikely to be the result of antidepressant treatment. These data suggest that levels of either mGlu2 and/or mGlu3 are affected in the aetiology of MDD.
Distinct transduction profiles in the CNS via three injection routes of AAV9 and the application to generation of a neurodegenerative mouse model
2014, Molecular Therapy Methods and Clinical Development
Using single-stranded adeno-associated virus serotype 9 (ssAAV9) vectors containing the neuron-specific synapsin-I promoter, we examined whether different administration routes (direct cerebellar cortical (DC), intrathecal (IT) and intravenous (IV) injections) could elicit specific transduction profiles in the CNS. The DC injection route robustly and exclusively transduced the whole cerebellum, whereas the IT injection route primarily transduced the cerebellar lobules 9 and 10 close to the injection site and the spinal cord. An IV injection in neonatal mice weakly and homogenously transduced broad CNS areas. In the cerebellar cortex, the DC and IT injection routes transduced all neuron types, whereas the IV injection route primarily transduced Purkinje cells. To verify the usefulness of this method, we generated a mouse model of spinocerebellar ataxia type 1 (SCA1). Mice that received a DC injection of the ssAAV9 vector expressing mutant ATXN1, a protein responsible for SCA1, showed the intranuclear aggregation of mutant ATXN1 in Purkinje cells, significant atrophy of the Purkinje cell dendrites and progressive motor deficits, which are characteristics of SCA1. Thus, ssAAV9-mediated transduction areas, levels, and cell types change depending on the route of injection. Moreover, this approach can be used for the generation of different mouse models of CNS/neurodegenerative diseases.

View all citing articles on Scopus

View full text

Metabotropic glutamate receptors mGluR2 and mGluR5 are expressed in two non-overlapping populations of Golgi cells in the rat cerebellum

Abstract

J. biol. Chem.

Neurosci. Lett.

Neurosci. Lett.

Neuroscience

Brain Res.

Brain Res.

Neuron

Neurosci. Lett.

Neuron

Neuroscience

Brain Res.

Neuropharmacology

Neurosci. Lett.

Neuron

Brain Res.