Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse

Neurobiology of Disease

Caroline Perronnet¹  Elise Peltekian¹  Luis Garcia¹  Jean-Marie Billard¹  Pascale Leblanc-Veyrac¹  Cyrille Vaillend²  Glenn Dallérac³  Nathalie Samson-Desvignes³  Carine Chagneau³  Olivier Danos³  Serge Laroche³ 

[1] CNRS, Orsay, F-91405, France;Institut de Myologie, Faculté de Médecine—Pitié Salpétrière, Université Pierre et Marie Curie Paris 6, Paris, France;Univ Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, F-91405, France;

关键词: Dystrophin;    Exon skipping;    Gene therapy;    Mdx mouse;    Synaptic plasticity;    Hippocampus;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 (GABAA)-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 GABAA-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 GABAA-receptor clustering and that re-expression of the otherwise deficient protein in the adult can significantly alleviate alteration of neural functions in DMD.

【 授权许可】

Unknown