Effects of phosphodiesterase inhibition on ERK phosphorylation in the R6/2 mouse model of Huntington’s disease

Introduction: ERK signaling has been implicated in a number of neurodegenerative disorders, including Huntington’s Disease(HD). Phosphorylation patterns of ERK and JNK are altered in cell models of HD. We have studied the correlations between ERK and the neuronal vulnerability to HD degeneration in the R6/2 transgenic mouse model of HD treated with the phosphodiesterase 4 inhibitor rolipram. Materials and methods: Immunohistochemistry for phospho-ERK (p-ERK, the activated form of ERK) and dual label immunofluorescence for p-ERK and each of the striatal neuronal markers were employed on perfusion-fixed brain sections from R6/2 and wild-tipe mice. Results: Striatal neurons, both spiny projection and interneurons, are completely devoid of p-ERK immunoreactivity in the wild-type mouse. Conversely, parvalbuminlabeled GABAergic interneurons of the striatum are highly enriched in p-ERK in the R6/2 mice, cholinergic and somatostatinergic interneurons are devoid of it. With rolipram treatment, p-ERK decreases in the parvaminergic neurons and in thecalbindin projection neurons of R6/2 mice. Discussion and conclusions: Our study confirms and extend the concept that the expression of phosphorilated ERK is related to neuronal vulnerability and is implicated in the pathophysiology of cell death in HD. Such concept is confirmed by the beneficial effects of rolipram in decreasing the levels of p-ERK in the more vulnerable neurons