Dystroglycan Mediates Clustering of Essential GABAergic Components in Cerebellar Purkinje Cells.

Federica Briatore,Annarita Patrizi,Maria Egle De Stefano,Giulia Pregno,Elena Frola,Silvia Di Angelantonio,Cyrille Vaillend,Marco Sassoè-Pognetto

doi:10.3389/fnmol.2020.00164

Abstract

Muscle dystrophin–glycoprotein complex (DGC) links the intracellular cytoskeleton to the extracellular matrix. In neurons, dystroglycan and dystrophin, two major components of the DGC, localize in a subset of GABAergic synapses, where their function is unclear. Here we used mouse models to analyze the specific role of the DGC in the organization and function of inhibitory synapses. Loss of full-length dystrophin in mdx mice resulted in a selective depletion of the transmembrane β-dystroglycan isoform from inhibitory post-synaptic sites in cerebellar Purkinje cells. Remarkably, there were no differences in the synaptic distribution of the extracellular α-dystroglycan subunit, of GABAA receptors and neuroligin 2. In contrast, conditional deletion of the dystroglycan gene from Purkinje cells caused a disruption of the DGC and severely impaired post-synaptic clustering of neuroligin 2, GABAA receptors and scaffolding proteins. Accordingly, whole-cell patch-clamp analysis revealed a significant reduction in the frequency and amplitude of spontaneous IPSCs recorded from Purkinje cells. In the long-term, deletion of dystroglycan resulted in a significant decrease of GABAergic innervation of Purkinje cells and caused an impairment of motor learning functions. These results show that dystroglycan is an essential synaptic organizer at GABAergic synapses in Purkinje cells.

Highlights

Synapse formation is a key step in the development of neuronal networks
We show that DG is required for post-synaptic localization of neuroligin 2 (NL2), GABAA receptors (GABAARs) and S-SCAM
Dystroglycan Is Essential for Assembly of the Dystrophin–Glycoprotein Complex in Purkinje Cells

Summary

Introduction

Research over the past few decades has led to the identification of several factors that play a role in the assembly, maturation and remodeling of synaptic connections, and provide a basis for the molecular and functional specificity of synapses (Shen and Scheiffele, 2010; Yogev and Shen, 2014). A substantial number of different synaptic cell-adhesion systems have been shown to control the formation of glutamatergic synapses, through specific PDZ-binding domains (Siddiqui and Craig, 2011). GABAergic synapses contain selective celladhesion proteins, such as neuroligin 2 (NL2) (Varoqueaux et al, 2004), and in some cases the dystrophin–glycoprotein complex (DGC) has been shown to play a role in inhibitory synaptic function (Anderson et al, 2003; Kueh et al, 2008; Pribiag et al, 2014)

Methods

Results

Conclusion