Metabotropic Glutamate Receptor-Mediated Cell Signaling Pathways Are Altered in a Mouse Model of Huntington's Disease
Copyright policy )Metabotropic Glutamate Receptor-Mediated Cell Signaling Pathways Are Altered in a Mouse Model of Huntington's Disease
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein (Htt). Group I metabotropic glutamate receptors (mGluRs) are coupled to Gαqand play an important role in neuronal survival. We have previously demonstrated that mGluRs interact with Htt. Here we used striatal neuronal primary cultures and acute striatal slices to demonstrate that mGluR-mediated signaling pathways are altered in a presymptomatic mouse model of HD (HdhQ111/Q111), as compared to those of control mice (HdhQ20/Q20). mGluR1/5-mediated inositol phosphate (InsP) formation is desensitized in striatal slices fromHdhQ111/Q111mice and this desensitization is PKC-mediated. Despite of decreased InsP formation, (S)-3,5-dihydroxylphenylglycine (DHPG)-mediated Ca2+release is higher inHdhQ111/Q111than inHdhQ20/Q20neurons. Furthermore, mGluR1/5-stimulated AKT and extracellular signal-regulated kinase (ERK) activation is altered inHdhQ111/Q111mice. Basal AKT activation is higher inHdhQ111/Q111neurons and this increase is mGluR5 dependent. Moreover, mGluR5 activation leads to higher levels of ERK activation inHdhQ111/Q111than inHdhQ20/Q20striatum. PKC inhibition not only bringsHdhQ111/Q111DHPG-stimulated InsP formation toHdhQ20/Q20levels, but also causes an increase in neuronal cell death inHdhQ111/Q111neurons. However, PKC inhibition does not modify neuronal cell death inHdhQ20/Q20neurons, suggesting that PKC-mediated desensitization of mGluR1/5 inHdhQ111/Q111mice might be protective in HD. Together, these data indicate that group I mGluR-mediated signaling pathways are altered in HD and that these cell signaling adaptations could be important for striatal neurons survival.
- Western University Canada
Disease Models, Animal, Mice, Huntington Disease, Animals, Mice, Transgenic, Gene Knock-In Techniques, Receptors, Metabotropic Glutamate, Cells, Cultured, Signal Transduction
Disease Models, Animal, Mice, Huntington Disease, Animals, Mice, Transgenic, Gene Knock-In Techniques, Receptors, Metabotropic Glutamate, Cells, Cultured, Signal Transduction
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