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Neurobiol Dis. 2018 Jan;109(Pt A):44-53. doi: 10.1016/j.nbd.2017.10.001. Epub 2017 Oct 2.

Genetic inactivation of mGlu5 receptor improves motor coordination in the Grm1crv4 mouse model of SCAR13 ataxia.

Author information

1
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, via Gaslini 5, 16148 Genoa, Italy.
2
Department of Pharmacy, Pharmacology and Toxicology Unit, University of Genoa, Viale Cembrano 4, 16148 Genoa, Italy.
3
Animal Facility, IRCCS A.U.O. San Martino-IST, Largo Rosanna Benzi 10, Genoa, Italy.
4
Department of Pharmacy, Pharmacology and Toxicology Unit, University of Genoa, Viale Cembrano 4, 16148 Genoa, Italy; Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV 9, 16132 Genoa, Italy.
5
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, via Gaslini 5, 16148 Genoa, Italy; Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV 9, 16132 Genoa, Italy; Medical Genetics Unit, Istituto Giannina Gaslini, via Gaslini 5, 16148 Genoa, Italy.
6
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, via Gaslini 5, 16148 Genoa, Italy; Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV 9, 16132 Genoa, Italy; Medical Genetics Unit, Istituto Giannina Gaslini, via Gaslini 5, 16148 Genoa, Italy. Electronic address: apuliti@unige.it.

Abstract

Deleterious mutations in the glutamate receptor metabotropic 1 gene (GRM1) cause a recessive form of cerebellar ataxia, SCAR13. GRM1 and GRM5 code for the metabotropic glutamate type 1 (mGlu1) and type 5 (mGlu5) receptors, respectively. Their different expression profiles suggest they could have distinct functional roles. In a previous study, homozygous mice lacking mGlu1 receptors (Grm1crv4/crv4) and exhibiting ataxia presented cerebellar overexpression of mGlu5 receptors, that was proposed to contribute to the mouse phenotype. To test this hypothesis, we here crossed Grm1crv4 and Grm5ko mice to generate double mutants (Grm1crv4/crv4Grm5ko/ko) lacking both mGlu1 and mGlu5 receptors. Double mutants and control mice were analyzed for spontaneous behavior and for motor activity by rotarod and footprint analyses. In the same mice, the release of glutamate from cerebellar nerve endings (synaptosomes) elicited by 12mM KCl or by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) was also evaluated. Motor coordination resulted improved in double mutants when compared to Grm1crv4/crv4 mice. Furthermore, in in vitro studies, glutamate release elicited by both KCl depolarization and activation of AMPA autoreceptors resulted reduced in Grm1crv4/crv4 mice compared to wild type mice, while it presented normal levels in double mutants. Moreover, we found that Grm1crv4/crv4 mice showed reduced expression of GluA2/3 AMPA receptor subunits in cerebellar synaptosomes, while it resulted restored to wild type level in double mutants. To conclude, blocking of mGlu5 receptor reduced the dysregulation of glutamate transmission and improved motor coordination in the Grm1crv4 mouse model of SCAR13, thus suggesting the possible usefulness of pharmacological therapies based on modulation of mGlu5 receptor activity for the treatment of this type of ataxia.

KEYWORDS:

AMPA receptors; Ataxia; Double mutant mice; Evoked glutamate release; Grm1(crv4) mouse; Mouse behavior analysis; Phenotype rescue; mGlu1 receptor; mGlu5 receptor

PMID:
28982591
DOI:
10.1016/j.nbd.2017.10.001
[Indexed for MEDLINE]

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