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 G(alphaq) and 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 (Hdh(Q111/Q111)), as compared to those of control mice (Hdh(Q20/Q20)). mGluR1/5-mediated inositol phosphate (InsP) formation is desensitized in striatal slices from Hdh(Q111/Q111) mice and this desensitization is PKC-mediated. Despite of decreased InsP formation, (S)-3,5-dihydroxylphenylglycine (DHPG)-mediated Ca(2+) release is higher in Hdh(Q111/Q111) than in Hdh(Q20/Q20) neurons. Furthermore, mGluR1/5-stimulated AKT and extracellular signal-regulated kinase (ERK) activation is altered in Hdh(Q111/Q111) mice. Basal AKT activation is higher in Hdh(Q111/Q111) neurons and this increase is mGluR5 dependent. Moreover, mGluR5 activation leads to higher levels of ERK activation in Hdh(Q111/Q111) than in Hdh(Q20/Q20) striatum. PKC inhibition not only brings Hdh(Q111/Q111) DHPG-stimulated InsP formation to Hdh(Q20/Q20) levels, but also causes an increase in neuronal cell death in Hdh(Q111/Q111) neurons. However, PKC inhibition does not modify neuronal cell death in Hdh(Q20/Q20) neurons, suggesting that PKC-mediated desensitization of mGluR1/5 in Hdh(Q111/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.
Ribeiro
Fabiola M
FM
Molecular Brain Research Group, Robarts Research Institute and Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5K8, Canada.
Paquet
Maryse
M
Ferreira
Lucimar T
LT
Cregan
Tamara
T
Swan
Patrick
P
Cregan
Sean P
SP
Ferguson
Stephen S G
SS
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006816:Huntington Disease / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D018094:Receptors, Metabotropic Glutamate