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1422-006723202022Oct20International journal of molecular sciencesInt J Mol SciAbnormal Expression of Synaptic and Extrasynaptic GABAA Receptor Subunits in the Dystrophin-Deficient mdx Mouse.1261710.3390/ijms232012617Duchenne muscular dystrophy (DMD) is a neurodevelopmental disorder primarily caused by the loss of the full-length Dp427 dystrophin in both muscle and brain. The basis of the central comorbidities in DMD is unclear. Brain dystrophin plays a role in the clustering of central gamma-aminobutyric acid A receptors (GABAARs), and its loss in the mdx mouse alters the clustering of some synaptic subunits in central inhibitory synapses. However, the diversity of GABAergic alterations in this model is still fragmentary. In this study, the analysis of in vivo PET imaging of a benzodiazepine-binding site radioligand revealed that the global density of central GABAARs is unaffected in mdx compared with WT mice. In contrast, semi-quantitative immunoblots and immunofluorescence confocal imaging in tissue sections revealed complex and differential patterns of alterations of the expression levels and/or clustered distribution of a variety of synaptic and extrasynaptic GABAAR subunits in the hippocampus, cerebellum, cortex, and spinal cord. Hence, dystrophin loss not only affects the stabilization of synaptic GABAARs but also influences the subunit composition of GABAARs subtypes at both synaptic and extrasynaptic sites. This study provides new molecular outcome measures and new routes to evaluate the impact of treatments aimed at compensating alterations of the nervous system in DMD.ZarroukiFaouziFUniversité Paris-Saclay, CNRS, Institut des Neurosciences Paris Saclay, 91400 Saclay, France.Université Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000 Versailles, France.GoutalSébastienSUniversité Paris-Saclay, INSERM, CNRS, CEA, Laboratoire d'Imagerie Biomédicale Multimodale (BioMaps), Service Hospitalier Frédéric Joliot, 91401 Orsay, France.VaccaOphélieO0000-0001-9281-843XUniversité Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000 Versailles, France.GarciaLuisLUniversité Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000 Versailles, France.TournierNicolasN0000-0002-0755-2030Université Paris-Saclay, INSERM, CNRS, CEA, Laboratoire d'Imagerie Biomédicale Multimodale (BioMaps), Service Hospitalier Frédéric Joliot, 91401 Orsay, France.GoyenvalleAurélieA0000-0003-3938-1165Université Paris-Saclay, UVSQ, Inserm, END-ICAP, 78000 Versailles, France.VaillendCyrilleC0000-0002-8783-8185Université Paris-Saclay, CNRS, Institut des Neurosciences Paris Saclay, 91400 Saclay, France.engN/AFrench National Centre for Scientific ResearchN/AInsermN/AUniversity of Paris-SaclayN/AConseil Régional d'Île-de-FranceN/AAssociation Monégasque contre les Myopathies (AMM, Monaco)PhD fellowshipFrench Muscular Dystrophy AssociationPhD fellowshipMinistry of Higher Education and Research847826European Union's Horizon 2020 research and innovationJournal Article20221020
SwitzerlandInt J Mol Sci1010927911422-00670Dystrophin0Receptors, GABA-A56-12-2gamma-Aminobutyric Acid12794-10-4BenzodiazepinesIMMiceAnimalsMice, Inbred mdxDystrophinmetabolismReceptors, GABA-AgeneticsmetabolismMice, Inbred C57BLMuscular Dystrophy, Duchennemetabolismgamma-Aminobutyric AcidmetabolismBenzodiazepinesDuchenne muscular dystrophyGABAA-receptor clusteringGABAergic synapsesPET brain imagingimmunofluorescenceoutcome measureswestern blotsThe authors declare no conflict of interest.2022718202292120221011202210271242022102860202210296020221020epublish36293496PMC960407310.3390/ijms232012617ijms232012617Desguerre I., Christov C., Mayer M., Zeller R., Becane H.-M., Bastuji-Garin S., Leturcq F., Chiron C., Chelly J., Gherardi R.K. Clinical Heterogeneity of Duchenne Muscular Dystrophy (DMD): Definition of Sub-Phenotypes and Predictive Criteria by Long-Term Follow-Up. 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