In-vivo genetic ablation of metabotropic glutamate receptor type 5 slows down disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis

Tiziana Bonifacino, Francesca Provenzano, Elena Gallia, Silvia Ravera, Carola Torazza, Simone Bossi, Sara Ferrando, Aldamaria Puliti, Ludo Van Den Bosch, Giambattista Bonanno, Marco Milanese

Research output: Contribution to journalArticle

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease due to motor neuron (MN) loss. The mechanisms causing selective MN death are largely unknown, thus prejudicing successful pharmacological treatments. Major causes of MN damage are effects downstream of the abnormal glutamate (Glu) neurotransmission. Group I metabotropic Glu receptors (mGluR1, mGluR5) actively contribute to the excitotoxicity in ALS and represent druggable molecular targets. We previously demonstrated that halving mGluR1 or mGluR5 expression in the widely studied SOD1 G93A mouse model of ALS had a positive impact on disease onset, clinical progression and survival, as well as on cellular and biochemical parameters altered in ALS. Whereas these effects were similar in female and male mGluR1 heterozygous SOD1 G93A mice, only male mGluR5 heterozygous SOD1 G93A mice showed improved motor skills during disease progression. To further validate the role of Group I mGluRs in ALS, we generated in this study mGluR1 or mGluR5 null mice expressing the SOD1 G93A mutation (SOD1 G93A Grm1 crv4/crv4 or SOD1 G93A Grm5 −/− , respectively). SOD1 G93A Grm1 crv4/crv4 mice showed early and progressive motor impairments and died even before SOD1 G93A mice, while SOD1 G93A Grm5 −/− mice exhibited delayed disease onset, longer survival, and ameliorated motor skills than SOD1 G93A mice. No difference between female and male SOD1 G93A Grm5 −/− mice were observed. These effects were associated with enhanced MN preservation and decreased astrocytic and microglial activation. Our results strongly support the assumption that constitutively lowering of mGluR5 expression has a positive impact in mice with ALS by counteracting the abnormal Glu transmission and this could be a potentially effective pharmacological target in ALS.

Original languageEnglish
Pages (from-to)79-92
Number of pages14
JournalNeurobiology of Disease
Volume129
DOIs
Publication statusPublished - Sep 1 2019

Keywords

  • Amyotrophic lateral sclerosis
  • Behaviour
  • Genetic ablation
  • Histology, disease progression
  • In-vivo
  • Metabotropic glutamate type 5 receptor
  • SOD1 mouse

ASJC Scopus subject areas

  • Neurology

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