Metabotropic glutamate receptor-mediated cell signaling pathways are altered in a mouse model of Huntington's disease

Abstract

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 toG αq and play an important role in neuronal survival. Wehave 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 (Hdh Q20/Q20). mGluR1/5-mediated inositol phosphate (InsP) formation is desensitized in striatal slices from HdhQ111/Q111 mice and this desensitization is PKC-mediated. Despite of decreased InsP formation, (S)-3,5-dihydroxylphenylglycine (DHPG)-mediated Ca2+ release is higher in HdhQ111/Q111 than in HdhQ20/Q20 neurons. Furthermore, mGluR1/5-stimulated AKT and extracellular signal-regulated kinase (ERK) activation is altered in HdhQ111/Q111 mice. Basal AKT activation is higher in HdhQ111/Q111 neurons and this increase is mGluR5 dependent. Moreover, mGluR5 activation leads to higher levels of ERK activation in HdhQ111/Q111 than in HdhQ20/Q20 striatum. PKC inhibition not only brings HdhQ111/Q111 DHPG-stimulated InsP formation to HdhQ20/Q20 levels, but also causes an increase in neuronal cell death in HdhQ111/Q111 neurons. However, PKC inhibition does not modify neuronal cell death in HdhQ20/Q20 neurons, suggesting that PKC-mediated desensitization of mGluR1/5 in HdhQ111/Q111 mice 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. Copyright © 2010 the authors.