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 GABAAreceptors. 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 GABAAreceptor 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 GABAAreceptor 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'.
authors: IRCCS Neuromed, Pozzilli, Italy.
authors: Serena
authors: S
authors: Notartomaso
authors: IRCCS Neuromed, Pozzilli, Italy.
authors: Giada
authors: G
authors: Mascio
authors: IRCCS Neuromed, Pozzilli, Italy.
authors: Pamela
authors: P
authors: Scarselli
authors: IRCCS Neuromed, Pozzilli, Italy.
authors: Katiuscia
authors: K
authors: Martinello
authors: IRCCS Neuromed, Pozzilli, Italy; Department of Physiology and Pharmacology, University Sapienza of Rome, Italy.
authors: Sergio
authors: S
authors: Fucile
authors: IRCCS Neuromed, Pozzilli, Italy; Department of Experimental Medicine, University Sapienza of Rome, Italy.
authors: Roberto
authors: R
authors: Gradini
authors: IRCCS Neuromed, Pozzilli, Italy; Department of Physiology and Pharmacology, University Sapienza of Rome, Italy.
authors: Valeria
authors: V
authors: Bruno
authors: IRCCS Neuromed, Pozzilli, Italy.
authors: Giuseppe
authors: G
authors: Battaglia
authors: IRCCS Neuromed, Pozzilli, Italy; Department of Physiology and Pharmacology, University Sapienza of Rome, Italy. Electronic address: ferdinandonicoletti@hotmail.com.
authors: Ferdinando
authors: F
authors: Nicoletti
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D015870:Gene Expression; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D027981:Symporters / Q000096:biosynthesis* / Q000235:genetics; D000096922:K Cl- Cotransporters
chemical_list: D018691:Excitatory Amino Acid Antagonists; D009536:Niacinamide; D018094:Receptors, Metabotropic Glutamate; D027981:Symporters; D000096922:K Cl- Cotransporters; C581972:N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide; C104077:metabotropic glutamate receptor type 1
keywords: Cerebellum; KCC2; Purkinje cells; mGlu1 receptor; mGlu5 receptors