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Dis Model Mech. 2018 Jun 12. pii: dmm.033258. doi: 10.1242/dmm.033258. [Epub ahead of print]

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

Author information

1
Paris-Saclay Institute of Neuroscience (Neuro-PSI), UMR 9197, Université Paris Sud, CNRS, Université Paris Saclay, Orsay, France.
2
Paris-Saclay Institute of Neuroscience (Neuro-PSI), UMR 9197, Université Paris Sud, CNRS, Université Paris Saclay, Orsay, France micaela.galante@u-psud.fr cyrille.vaillend@u-psud.fr.

Abstract

A recent focus has been placed on the role that cerebellar dysfunctions could play 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, which 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 (PFs). Altered basal neurotransmission at CFs was associated with impairments in synaptic plasticity and clustering of the scaffolding post-synaptic 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. However, Dp71-null mice displayed altered strategies in goal-oriented navigation tasks, suggesting a deficit in the cerebellum-dependent processing of the procedural components of spatial learning which could contribute to the visuo-spatial 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.

KEYWORDS:

Cerebellum; Cognitive deficit; Dystrophin Dp71; Glutamatergic transmission; Motor coordination; Purkinje neuron

PMID:
29895670
DOI:
10.1242/dmm.033258
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