MGlu1 Receptors Monopolize the Synaptic Control of Cerebellar Purkinje Cells by Epigenetically Down-Regulating mGlu5 Receptors

Serena Notartomaso,Giuseppe Battaglia,Valeria Bruno,Micaela Zonta,Milena Cannella,Masahiko Watanabe,Michele Madonna,Francesca Liberatore,Giada Mascio,Giorgio Carmignoto,Harumi Nakao,Pamela Scarselli,Cristina Zappulla,Roberto Gradini,Ferdinando Nicoletti,Atsu Aiba,Marta Motolese

doi:10.1038/s41598-018-31369-7

Abstract

In cerebellar Purkinje cells (PCs) type-1 metabotropic glutamate (mGlu1) receptors play a key role in motor learning and drive the refinement of synaptic innervation during postnatal development. The cognate mGlu5 receptor is absent in mature PCs and shows low expression levels in the adult cerebellar cortex. Here we found that mGlu5 receptors were heavily expressed by PCs in the early postnatal life, when mGlu1α receptors were barely detectable. The developmental decline of mGlu5 receptors coincided with the appearance of mGlu1α receptors in PCs, and both processes were associated with specular changes in CpG methylation in the corresponding gene promoters. It was the mGlu1 receptor that drove the elimination of mGlu5 receptors from PCs, as shown by data obtained with conditional mGlu1α receptor knockout mice and with targeted pharmacological treatments during critical developmental time windows. The suppressing activity of mGlu1 receptors on mGlu5 receptor was maintained in mature PCs, suggesting that expression of mGlu1α and mGlu5 receptors is mutually exclusive in PCs. These findings add complexity to the the finely tuned mechanisms that regulate PC biology during development and in the adult life and lay the groundwork for an in-depth analysis of the role played by mGlu5 receptors in PC maturation.

Highlights

Impairment of long-term depression (LTD) at parallel fiber-PC synapses associated with a profound defect in the conditioned eyeblink reflex and motor coordination
We were intrigued by the finding that mGlu[5] receptor protein levels in the rat cerebellum are higher in the early postnatal life than in the adult life, as opposed to mGlu1α receptor protein levels, which are more abundant in the adulthood than at PND928
We report that mGlu[5] receptors are highly expressed by cerebellar PCs in the first 12 days of postnatal life, and that the developmental decline in mGlu[5] receptor expression coincides with the appearance and up-regulation of mGlu1α receptors

Summary

Introduction

Impairment of long-term depression (LTD) at parallel fiber-PC synapses associated with a profound defect in the conditioned eyeblink reflex and motor coordination. As opposed to mGlu[1] receptors, mGlu[5] receptors are virtually absent in mature cerebellar PCs, and show low expression levels in the adult cerebellar cortex, being mainly localized in Lugaro and Golgi cells[22,23] This dampened the interest for the study of mGlu[5] receptors in the cerebellum, changes in cerebellar mGlu[5] receptor expression were found in autoptic tissues from individuals affected by psychiatric disorders, autism, and Fragile X-associated tremor/ataxia syndrome[24,25,26,27]. We were intrigued by the finding that mGlu[5] receptor protein levels in the rat cerebellum are higher in the early postnatal life than in the adult life, as opposed to mGlu1α receptor protein levels, which are more abundant in the adulthood than at PND928. We demonstrate that it is the mGlu[1] receptor that down-regulates the expression of mGlu[5] receptors during the development of PCs and maintains its suppressing activity in the adult life

Methods

Results

Conclusion