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

38 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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