Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse
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 inhib...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2011-09-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996111001689 |
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| author | Glenn Dallérac Caroline Perronnet Carine Chagneau Pascale Leblanc-Veyrac Nathalie Samson-Desvignes Elise Peltekian Olivier Danos Luis Garcia Serge Laroche Jean-Marie Billard Cyrille Vaillend |
| author_facet | Glenn Dallérac Caroline Perronnet Carine Chagneau Pascale Leblanc-Veyrac Nathalie Samson-Desvignes Elise Peltekian Olivier Danos Luis Garcia Serge Laroche Jean-Marie Billard Cyrille Vaillend |
| author_sort | Glenn Dallérac |
| collection | DOAJ |
| description | 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. |
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| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-18T02:07:04Z |
| publishDate | 2011-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-ad0169baae5b421f99d7a1086b84a6572022-12-21T21:24:34ZengElsevierNeurobiology of Disease1095-953X2011-09-01433635641Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouseGlenn Dallérac0Caroline Perronnet1Carine Chagneau2Pascale Leblanc-Veyrac3Nathalie Samson-Desvignes4Elise Peltekian5Olivier Danos6Luis Garcia7Serge Laroche8Jean-Marie Billard9Cyrille Vaillend10Univ Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, F-91405, France; CNRS, Orsay, F-91405, FranceUniv Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, F-91405, France; CNRS, Orsay, F-91405, FranceUniv Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, F-91405, France; CNRS, Orsay, F-91405, FranceUniv Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, F-91405, France; CNRS, Orsay, F-91405, FranceUniv Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, F-91405, France; CNRS, Orsay, F-91405, FranceInstitut de Myologie, Faculté de Médecine—Pitié Salpétrière, Université Pierre et Marie Curie Paris 6, Paris, France; Unité Mixte de Recherche UPMC-AIM, UMR S974, INSERM U974, CNRS UMR 7215, Paris, FranceHôpital Necker-Enfants malades, Université Paris Descartes, 75743 Paris Cedex 15, France; INSERM U845, Paris, France; Cancer Institute, University College London, UKInstitut de Myologie, Faculté de Médecine—Pitié Salpétrière, Université Pierre et Marie Curie Paris 6, Paris, France; Unité Mixte de Recherche UPMC-AIM, UMR S974, INSERM U974, CNRS UMR 7215, Paris, FranceUniv Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, F-91405, France; CNRS, Orsay, F-91405, FranceNeurobiologie du Vieillissement Normal et Pathologique, Centre de Psychiatrie et Neurosciences, UMR 894, Université Paris Descartes, 2 ter rue d'Alésia, 75014 Paris, FranceUniv Paris-Sud, Centre de Neurosciences Paris-Sud, UMR 8195, Orsay, F-91405, France; CNRS, Orsay, F-91405, France; Corresponding author at: Centre de Neurosciences Paris-Sud, Université Paris-Sud XI, CNRS-UMR8195, 91405, Orsay, France. Fax: +33 169157726.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.http://www.sciencedirect.com/science/article/pii/S0969996111001689DystrophinExon skippingGene therapyMdx mouseSynaptic plasticityHippocampus |
| spellingShingle | Glenn Dallérac Caroline Perronnet Carine Chagneau Pascale Leblanc-Veyrac Nathalie Samson-Desvignes Elise Peltekian Olivier Danos Luis Garcia Serge Laroche Jean-Marie Billard Cyrille Vaillend Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse Neurobiology of Disease Dystrophin Exon skipping Gene therapy Mdx mouse Synaptic plasticity Hippocampus |
| title | Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse |
| title_full | Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse |
| title_fullStr | Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse |
| title_full_unstemmed | Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse |
| title_short | Rescue of a dystrophin-like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse |
| title_sort | rescue of a dystrophin like protein by exon skipping normalizes synaptic plasticity in the hippocampus of the mdx mouse |
| topic | Dystrophin Exon skipping Gene therapy Mdx mouse Synaptic plasticity Hippocampus |
| url | http://www.sciencedirect.com/science/article/pii/S0969996111001689 |
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