title: Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse.
abstract: Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, a protein that fulfills important functions in both muscle and brain. The mdx mouse model of DMD, which also lacks dystrophin, shows a marked reduction in γ-aminobutyric acid type A (GABA(A))-receptor clustering in central inhibitory synapses and enhanced long-term potentiation (LTP) at CA3-CA1 synapses of the hippocampus. We have recently shown that U7 small nuclear RNAs modified to encode antisense sequences and expressed from recombinant adeno-associated viral (rAAV) vectors are able to induce skipping of the mutated exon 23 and to rescue expression of a functional dystrophin-like product both in the muscle and nervous tissue in vivo. In the brain, this rescue was accompanied by restoration of both the size and number of hippocampal GABA(A)-receptor clustering. Here, we report that 25.2±8% of re-expression two months after intrahippocampal injection of rAAV reverses the abnormally enhanced LTP phenotype at CA3-CA1 synapses of mdx mice. These results suggests that dystrophin expression indirectly influences synaptic plasticity through modulation of GABA(A)-receptor clustering and that re-expression of the otherwise deficient protein in the adult can significantly alleviate alteration of neural functions in DMD.
authors.affiliation: Univ Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay F-91405, France.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dallérac
authors.forename: Caroline
authors.initials: C
authors.lastname: Perronnet
authors.forename: Carine
authors.initials: C
authors.lastname: Chagneau
authors.forename: Pascale
authors.initials: P
authors.lastname: Leblanc-Veyrac
authors.forename: Nathalie
authors.initials: N
authors.lastname: Samson-Desvignes
authors.forename: Elise
authors.initials: E
authors.lastname: Peltekian
authors.forename: Olivier
authors.initials: O
authors.lastname: Danos
authors.forename: Luis
authors.initials: L
authors.lastname: Garcia
authors.forename: Serge
authors.initials: S
authors.lastname: Laroche
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Billard
authors.forename: Cyrille
authors.initials: C
authors.lastname: Vaillend
mesh_terms: D000367:Age Factors; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D016189:Dystrophin / Q000235:genetics*; D005071:Evoked Potentials / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006624:Hippocampus / Q000502:physiology*; D017774:Long-Term Potentiation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D009433:Neural Inhibition / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics*; D009924:Organ Culture Techniques; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000235:genetics*
chemical_list: D016189:Dystrophin; D011963:Receptors, GABA-A