Expression of the K+/Cl- cotransporter, KCC2, in cerebellar Purkinje cells is regulated by group-I metabotropic glutamate receptors

Serena Notartomaso, Giada Mascio, Pamela Scarselli, Katiuscia Martinello, Sergio Fucile, Roberto Gradini, Valeria Bruno, Giuseppe Battaglia, Ferdinando Nicoletti

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3 Citations (Scopus)

Abstract

The neuronal K+/Cl- symporter, KCC2, shapes synaptic responses mediated by Cl--permeant GABAA 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 GABAA 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 GABAA 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.

Original languageEnglish
JournalNeuropharmacology
DOIs
Publication statusAccepted/In press - Mar 30 2016

Fingerprint

Metabotropic Glutamate Receptors
Purkinje Cells
Cerebellum
GABA-A Receptors
GABA-A Receptor Agonists
Symporters
Muscimol
Diazepam
Synaptic Transmission
gamma-Aminobutyric Acid
Action Potentials
potassium-chloride symporters
Proteins
Pharmacology
Ligands
Neurons
Pharmaceutical Preparations

Keywords

  • Cerebellum
  • KCC2
  • MGlu1 receptor
  • MGlu5 receptors
  • Purkinje cells

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

@article{16d90264524240128927877195f19541,
title = "Expression of the K+/Cl- cotransporter, KCC2, in cerebellar Purkinje cells is regulated by group-I metabotropic glutamate receptors",
abstract = "The neuronal K+/Cl- symporter, KCC2, shapes synaptic responses mediated by Cl--permeant GABAA 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 GABAA 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 GABAA 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.",
keywords = "Cerebellum, KCC2, MGlu1 receptor, MGlu5 receptors, Purkinje cells",
author = "Serena Notartomaso and Giada Mascio and Pamela Scarselli and Katiuscia Martinello and Sergio Fucile and Roberto Gradini and Valeria Bruno and Giuseppe Battaglia and Ferdinando Nicoletti",
year = "2016",
month = "3",
day = "30",
doi = "10.1016/j.neuropharm.2016.07.032",
language = "English",
journal = "Neuropharmacology",
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TY - JOUR

T1 - Expression of the K+/Cl- cotransporter, KCC2, in cerebellar Purkinje cells is regulated by group-I metabotropic glutamate receptors

AU - Notartomaso, Serena

AU - Mascio, Giada

AU - Scarselli, Pamela

AU - Martinello, Katiuscia

AU - Fucile, Sergio

AU - Gradini, Roberto

AU - Bruno, Valeria

AU - Battaglia, Giuseppe

AU - Nicoletti, Ferdinando

PY - 2016/3/30

Y1 - 2016/3/30

N2 - The neuronal K+/Cl- symporter, KCC2, shapes synaptic responses mediated by Cl--permeant GABAA 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 GABAA 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 GABAA 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.

AB - The neuronal K+/Cl- symporter, KCC2, shapes synaptic responses mediated by Cl--permeant GABAA 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 GABAA 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 GABAA 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.

KW - Cerebellum

KW - KCC2

KW - MGlu1 receptor

KW - MGlu5 receptors

KW - Purkinje cells

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