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

Simone Bossi, Ilaria Musante, Tommaso Bonfiglio, Tiziana Bonifacino, Laura Emionite, Maria Cerminara, Chiara Cervetto, Manuela Marcoli, Giambattista Bonanno, Roberto Ravazzolo, Anna Pittaluga, Aldamaria Puliti

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)44-53
Number of pages10
JournalNeurobiology of Disease
Volume109
Issue numberPt A
DOIs
Publication statusPublished - Jan 2018

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Ataxia
Glutamic Acid
Cerebellar Ataxia
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Synaptosomes
Metabotropic Glutamate 5 Receptor
Isoxazoles
Autoreceptors
AMPA Receptors
Nerve Endings
Genes
Motor Activity
Pharmacology
Phenotype
Mutation

Keywords

  • Animals
  • Autoreceptors/metabolism
  • Cerebellar Ataxia/genetics
  • Cerebellum/metabolism
  • Disease Models, Animal
  • Female
  • Glutamic Acid/metabolism
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity
  • Phenotype
  • Protein Subunits
  • Receptor, Metabotropic Glutamate 5/genetics
  • Receptors, AMPA/metabolism
  • Receptors, Metabotropic Glutamate/genetics
  • Rotarod Performance Test

Cite this

Genetic inactivation of mGlu5 receptor improves motor coordination in the Grm1crv4 mouse model of SCAR13 ataxia. / Bossi, Simone; Musante, Ilaria; Bonfiglio, Tommaso; Bonifacino, Tiziana; Emionite, Laura; Cerminara, Maria; Cervetto, Chiara; Marcoli, Manuela; Bonanno, Giambattista; Ravazzolo, Roberto; Pittaluga, Anna; Puliti, Aldamaria.

In: Neurobiology of Disease, Vol. 109, No. Pt A, 01.2018, p. 44-53.

Research output: Contribution to journalArticle

Bossi, S, Musante, I, Bonfiglio, T, Bonifacino, T, Emionite, L, Cerminara, M, Cervetto, C, Marcoli, M, Bonanno, G, Ravazzolo, R, Pittaluga, A & Puliti, A 2018, 'Genetic inactivation of mGlu5 receptor improves motor coordination in the Grm1crv4 mouse model of SCAR13 ataxia', Neurobiology of Disease, vol. 109, no. Pt A, pp. 44-53. https://doi.org/10.1016/j.nbd.2017.10.001
Bossi, Simone ; Musante, Ilaria ; Bonfiglio, Tommaso ; Bonifacino, Tiziana ; Emionite, Laura ; Cerminara, Maria ; Cervetto, Chiara ; Marcoli, Manuela ; Bonanno, Giambattista ; Ravazzolo, Roberto ; Pittaluga, Anna ; Puliti, Aldamaria. / Genetic inactivation of mGlu5 receptor improves motor coordination in the Grm1crv4 mouse model of SCAR13 ataxia. In: Neurobiology of Disease. 2018 ; Vol. 109, No. Pt A. pp. 44-53.
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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.",
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T1 - Genetic inactivation of mGlu5 receptor improves motor coordination in the Grm1crv4 mouse model of SCAR13 ataxia

AU - Bossi, Simone

AU - Musante, Ilaria

AU - Bonfiglio, Tommaso

AU - Bonifacino, Tiziana

AU - Emionite, Laura

AU - Cerminara, Maria

AU - Cervetto, Chiara

AU - Marcoli, Manuela

AU - Bonanno, Giambattista

AU - Ravazzolo, Roberto

AU - Pittaluga, Anna

AU - Puliti, Aldamaria

N1 - Copyright © 2017 Elsevier Inc. All rights reserved.

PY - 2018/1

Y1 - 2018/1

N2 - 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.

AB - 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.

KW - Animals

KW - Autoreceptors/metabolism

KW - Cerebellar Ataxia/genetics

KW - Cerebellum/metabolism

KW - Disease Models, Animal

KW - Female

KW - Glutamic Acid/metabolism

KW - Male

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Motor Activity

KW - Phenotype

KW - Protein Subunits

KW - Receptor, Metabotropic Glutamate 5/genetics

KW - Receptors, AMPA/metabolism

KW - Receptors, Metabotropic Glutamate/genetics

KW - Rotarod Performance Test

U2 - 10.1016/j.nbd.2017.10.001

DO - 10.1016/j.nbd.2017.10.001

M3 - Article

C2 - 28982591

VL - 109

SP - 44

EP - 53

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

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