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

Abstract

Recent 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.

Dp71 contribution to the molecular scaffold anchoring aquaporine‐4 channels in brain macroglial cells

“…Converging evidence indicate that the loss of Dp71 impairs the clustering of aquaporin (AQP4) water channels in the glial endfeet adjacent to capillaries, which may induce critical alterations in water and ion brain homeostasis, vascular permeability, synaptic plasticity, and cognitive functions (Amiry‐Moghaddam, Hoddevik, & Ottersen, 2010; Hubbard et al, 2018). In the present study, we studied the Dp71‐null mouse in order to characterize the altered distribution of AQP4 channels in main brain structures that have been associated with cognitive and neurophysiological defects in this mouse, the cerebellum (Helleringer et al, 2018), hippocampus, and cortex (Chaussenot et al, 2019; Daoud, Candelario‐Martínez, et al, 2009). We found a residual expression of AQP4 in selective layers of these brain structures and in specific gliovascular elements, thus highlighting that the loss of Dp71 cannot fully recapitulate the glial and vascular alterations reported in AQP4‐KO mice.…”

“…The loss of Dp71 is a pivotal aggravating factor for cognitive status in DMD (Daoud et al, 2009), which frequently associates intellectual disability (ID) and neuropsychiatric disturbances such as autism‐spectrum disorders (Ricotti et al, 2016). Recent studies in mice with a selective loss of Dp71 (Dp71‐null mice) unveiled presence of specific cognitive and executive deficits associated with unbalanced neuronal network excitability and impaired plasticity in various brain structures involved in cognitive processes (Chaussenot, Amar, Fossier, & Vaillend, 2019; Daoud et al, 2009; Helleringer et al, 2018). However, the molecular and cellular mechanisms underlying Dp71‐dependent brain dysfunctions are poorly understood.…”

Dystroglycan Mediates Clustering of Essential GABAergic Components in Cerebellar Purkinje Cells

“…The latency to touch the wire with one hind paw were recorded during each trial; a mean score was then calculated. Other qualitive parameters were recorded and a score was attributed corresponding to the best performance achieved within the minute of testing according to the following scale ( Helleringer et al, 2018 ): (0) fell off; (1) clung to the bar with two forepaws; (2) attempted to climb on to the bar besides clinging to it with two forepaws; (3) hung on to the bar with two forepaws and one or both hind paws; (4) hung on to the bar with all four paws with the tail additionally wrapped around the bar; (5) escaped to one of the supports.…”

Defects of full-length dystrophin trigger retinal neuron damage and synapse alterations by disrupting functional autophagy

“…Since dys gene is evolutionarily well conserved, a number of animal models of DMD have been described including mouse, dog, zebrafish, the nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster [11][12][13]. In the last decade, several studies in vertebrate and invertebrate model systems highlighted the role of DGC and/or dystrophin variants at both peripheral and central synapses; as for instance, in the development of nervous structures, including the retina, in the maturation of neurotransmitter-receptor complexes and in the regulation of neurotransmitter release, in the modulation of excitatory/inhibitory signaling of neurons and in neuronal density of the brain [7,8,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. In the human nervous system, large changes in the expression of multiple dystrophin isoforms occur throughout life cycle especially between the fetal and adult brain [3], thus suggesting the cell-type specific function of distinct dystrophin variants across nervous regions.…”