Modulation of mGluR1 signaling improves Purkinje cell dysfunction associated with spinocerebellar ataxia 14

Spinocerebellar ataxia type 14 (SCA14) is caused by mutations in protein kinase C gamma (PKCγ) that lead to constitutive kinase activity and Purkinje cell dysfunction in the cerebellum. PKCγ acts downstream of metabotropic glutamate receptor 1 (mGluR1) signaling; however, it remains unclear whether alterations in this upstream pathway contribute to the cellular defects induced by mutant PKCγ. Here, we investigated the role of mGluR1 signaling in PKCγ-dependent pathology using organotypic cerebellar slice cultures from a mouse model of SCA14. Modulation of mGluR1 signaling partially improved dendritic abnormalities and dendritic spine phenotypes associated with constitutive PKCγ activation. In addition, inhibition of mGluR1 reduced phosphorylation of PKC substrates and restored the enrichment of scaffold proteins and their synaptic proximity to mGluR1. Together, our results demonstrate that mGluR1 signaling contributes to Purkinje cell abnormalities induced by constitutive PKCγ activity and that modulation of mGluR1 can improve disease-associated cellular phenotypes in SCA14.