Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1

Serena Notartomaso, Cristina Zappulla, Francesca Biagioni, Milena Cannella, Domenico Bucci, Giada Mascio, Pamela Scarselli, Francesco Fazio, Filippo Weisz, Luana Lionetto, Maurizio Simmaco, Roberto Gradini, Giuseppe Battaglia, Michele Signore, Aldamaria Puliti, Ferdinando Nicoletti

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background: Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1. Results: Symptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells. Conclusions: These data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel "cerebellum-specific", effective, and safe symptomatic drugs for the treatment of SCA1 in humans.

Original languageEnglish (US)
Article number48
JournalMolecular Brain
Volume6
Issue number1
DOIs
StatePublished - Nov 19 2013
Externally publishedYes

Fingerprint

Spinocerebellar Ataxias
Metabotropic Glutamate Receptors
Pharmacology
Cerebellum
Purkinje Cells
Pharmaceutical Preparations
Inborn Genetic Diseases
Neuronal Plasticity
AMPA Receptors
Ataxia
Dendrites
Transgenic Mice
Spine
Therapeutics
Messenger RNA
Injections

Keywords

  • JNJ16259685
  • mGlu1 receptor
  • mGlu5 receptor
  • Motor coordination
  • Purkinje cell
  • Ro0711401
  • Spinocerebellar ataxia type 1
  • VU0360172

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1. / Notartomaso, Serena; Zappulla, Cristina; Biagioni, Francesca; Cannella, Milena; Bucci, Domenico; Mascio, Giada; Scarselli, Pamela; Fazio, Francesco; Weisz, Filippo; Lionetto, Luana; Simmaco, Maurizio; Gradini, Roberto; Battaglia, Giuseppe; Signore, Michele; Puliti, Aldamaria; Nicoletti, Ferdinando.

In: Molecular Brain, Vol. 6, No. 1, 48, 19.11.2013.

Research output: Contribution to journalArticle

Notartomaso, S, Zappulla, C, Biagioni, F, Cannella, M, Bucci, D, Mascio, G, Scarselli, P, Fazio, F, Weisz, F, Lionetto, L, Simmaco, M, Gradini, R, Battaglia, G, Signore, M, Puliti, A & Nicoletti, F 2013, 'Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1', Molecular Brain, vol. 6, no. 1, 48. https://doi.org/10.1186/1756-6606-6-48
Notartomaso, Serena ; Zappulla, Cristina ; Biagioni, Francesca ; Cannella, Milena ; Bucci, Domenico ; Mascio, Giada ; Scarselli, Pamela ; Fazio, Francesco ; Weisz, Filippo ; Lionetto, Luana ; Simmaco, Maurizio ; Gradini, Roberto ; Battaglia, Giuseppe ; Signore, Michele ; Puliti, Aldamaria ; Nicoletti, Ferdinando. / Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1. In: Molecular Brain. 2013 ; Vol. 6, No. 1.
@article{25dd6d2aa0314956ba0d5058eadf1d28,
title = "Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1",
abstract = "Background: Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1. Results: Symptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells. Conclusions: These data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel {"}cerebellum-specific{"}, effective, and safe symptomatic drugs for the treatment of SCA1 in humans.",
keywords = "JNJ16259685, mGlu1 receptor, mGlu5 receptor, Motor coordination, Purkinje cell, Ro0711401, Spinocerebellar ataxia type 1, VU0360172",
author = "Serena Notartomaso and Cristina Zappulla and Francesca Biagioni and Milena Cannella and Domenico Bucci and Giada Mascio and Pamela Scarselli and Francesco Fazio and Filippo Weisz and Luana Lionetto and Maurizio Simmaco and Roberto Gradini and Giuseppe Battaglia and Michele Signore and Aldamaria Puliti and Ferdinando Nicoletti",
year = "2013",
month = "11",
day = "19",
doi = "10.1186/1756-6606-6-48",
language = "English (US)",
volume = "6",
journal = "Molecular Brain",
issn = "1756-6606",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1

AU - Notartomaso, Serena

AU - Zappulla, Cristina

AU - Biagioni, Francesca

AU - Cannella, Milena

AU - Bucci, Domenico

AU - Mascio, Giada

AU - Scarselli, Pamela

AU - Fazio, Francesco

AU - Weisz, Filippo

AU - Lionetto, Luana

AU - Simmaco, Maurizio

AU - Gradini, Roberto

AU - Battaglia, Giuseppe

AU - Signore, Michele

AU - Puliti, Aldamaria

AU - Nicoletti, Ferdinando

PY - 2013/11/19

Y1 - 2013/11/19

N2 - Background: Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1. Results: Symptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells. Conclusions: These data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel "cerebellum-specific", effective, and safe symptomatic drugs for the treatment of SCA1 in humans.

AB - Background: Spinocerebellar ataxia type 1 (SCA1) is a genetic disorder characterized by severe ataxia associated with progressive loss of cerebellar Purkinje cells. The mGlu1 metabotropic glutamate receptor plays a key role in mechanisms of activity-dependent synaptic plasticity in the cerebellum, and its dysfunction is linked to the pathophysiology of motor symptoms associated with SCA1. We used SCA1 heterozygous transgenic mice (Q154/Q2) as a model for testing the hypothesis that drugs that enhance mGlu1 receptor function may be good candidates for the medical treatment of SCA1. Results: Symptomatic 30-week old SCA1 mice showed reduced mGlu1 receptor mRNA and protein levels in the cerebellum. Interestingly, these mice also showed an intense expression of mGlu5 receptors in cerebellar Purkinje cells, which normally lack these receptors. Systemic treatment of SCA1 mice with the mGlu1 receptor positive allosteric modulator (PAM), Ro0711401 (10 mg/kg, s.c.), caused a prolonged improvement of motor performance on the rotarod and the paw-print tests. A single injection of Ro0711401 improved motor symptoms for several days, and no tolerance developed to the drug. In contrast, the mGlu5 receptor PAM, VU0360172 (10 mg/kg, s.c.), caused only a short-lasting improvement of motor symptoms, whereas the mGlu1 receptor antagonist, JNJ16259685 (2.5 mg/kg, i.p.), further impaired motor performance in SCA1 mice. The prolonged symptomatic benefit caused by Ro0711401 outlasted the time of drug clearance from the cerebellum, and was associated with neuroadaptive changes in the cerebellum, such as a striking reduction of the ectopically expressed mGlu5 receptors in Purkinje cells, increases in levels of total and Ser880-phosphorylated GluA2 subunit of AMPA receptors, and changes in the length of spines in the distal dendrites of Purkinje cells. Conclusions: These data demonstrate that pharmacological enhancement of mGlu1 receptors causes a robust and sustained motor improvement in SCA1 mice, and lay the groundwork for the development of mGlu1 receptor PAMs as novel "cerebellum-specific", effective, and safe symptomatic drugs for the treatment of SCA1 in humans.

KW - JNJ16259685

KW - mGlu1 receptor

KW - mGlu5 receptor

KW - Motor coordination

KW - Purkinje cell

KW - Ro0711401

KW - Spinocerebellar ataxia type 1

KW - VU0360172

UR - http://www.scopus.com/inward/record.url?scp=84887750408&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887750408&partnerID=8YFLogxK

U2 - 10.1186/1756-6606-6-48

DO - 10.1186/1756-6606-6-48

M3 - Article

C2 - 24252411

AN - SCOPUS:84887750408

VL - 6

JO - Molecular Brain

JF - Molecular Brain

SN - 1756-6606

IS - 1

M1 - 48

ER -