Cerebellar synapse properties and cerebellum-dependent motor and non-motor performance in Dp71-null mice.

Romain Helleringer,Charlotte Izabelle,Delphine Le Verger,Mehdi Belmaati-Cherkaoui,Hervé Daniel,Xia Li,Raoudha Dammak,Rémi Chaussenot,Cyrille Vaillend,Micaela Galante,Paulette Decottignies

doi:10.1242/dmm.033258

Abstract

ABSTRACTRecent emphasis has been placed on the role that cerebellar dysfunctions could have in the genesis of cognitive deficits in Duchenne muscular dystrophy (DMD). However, relevant genotype-phenotype analyses are missing to define whether cerebellar defects underlie the severe cases of intellectual deficiency that have been associated with genetic loss of the smallest product of the dmd gene, the Dp71 dystrophin. To determine for the first time whether Dp71 loss could affect cerebellar physiology and functions, we have used patch-clamp electrophysiological recordings in acute cerebellar slices and a cerebellum-dependent behavioral test battery addressing cerebellum-dependent motor and non-motor functions in Dp71-null transgenic mice. We found that Dp71 deficiency selectively enhances excitatory transmission at glutamatergic synapses formed by climbing fibers (CFs) on Purkinje neurons, but not at those formed by parallel fibers. Altered basal neurotransmission at CFs was associated with impairments in synaptic plasticity and clustering of the scaffolding postsynaptic density protein PSD-95. At the behavioral level, Dp71-null mice showed some improvements in motor coordination and were unimpaired for muscle force, static and dynamic equilibrium, motivation in high-motor demand and synchronization learning. Dp71-null mice displayed altered strategies in goal-oriented navigation tasks, however, suggesting a deficit in the cerebellum-dependent processing of the procedural components of spatial learning, which could contribute to the visuospatial deficits identified in this model. In all, the observed deficits suggest that Dp71 loss alters cerebellar synapse function and cerebellum-dependent navigation strategies without being detrimental for motor functions.

Highlights

The Duchenne muscular dystrophy gene has at least 8 promoters driving expression of distinct dystrophin proteins that are components of different multiprotein complexes linking cytoskeletal actin to cell membrane proteins in a variety of tissues
Mutations in the dmd gene are responsible for Duchenne muscular dystrophy (DMD) syndrome, in which muscular degeneration is associated with cognitive deficits presumably owing to the loss of dystrophin gene products that are normally expressed in the brain (Kim et al, 1995; Desguerre et al, 2009)
excitatory postsynaptic currents (EPSC) were identified as parallel fibers (PFs)-induced EPSCs (PF-EPSCs) when their amplitude increased in a graded manner with stimulus intensity and when they displayed paired-pulse facilitation (PPF) (Fig. 1A,B)

Summary

Introduction

The Duchenne muscular dystrophy (dmd) gene has at least 8 promoters driving expression of distinct dystrophin proteins that are components of different multiprotein complexes linking cytoskeletal actin to cell membrane proteins in a variety of tissues. Five downstream promoters give rise to shorter dystrophin products (Dp260, Dp140, Dp116 and Dp71) with cell-specific expression in various organs including the nervous system (Perronnet and Vaillend, 2010; Hendriksen et al, 2015). Mutations in the dmd gene are responsible for Duchenne muscular dystrophy (DMD) syndrome, in which muscular degeneration is associated with cognitive deficits presumably owing to the loss of dystrophin gene products that are normally expressed in the brain (Kim et al, 1995; Desguerre et al, 2009). Mutations in the first exons that selectively affect expression of Dp427 lead to moderate cognitive deficits, whereas in about one-third of patients downstream mutations inducing a cumulative loss of the shorter dystrophin products are responsible for moderate to severe intellectual disability (Desguerre et al, 2009). Dp71 loss appears to be a pivotal aggravating factor, as patients with impaired expression of Dp71 are most severely affected and systematically show intelligence quotients (IQs) below 70 (Daoud et al, 2009a)

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