Juvenile AAV-Mediated MEF2C Gene Replacement Ameliorates Selected Phenotypes in Mef2c-Haploinsufficient Mice
- 1Songjiang Research Institute, Shanghai Jiao Tong University School of Medicine
Abstract
MEF2C haploinsufficiency syndrome is a severe neurodevelopmental disorder for which no disease-directed treatment is available. We investigated whether neuron-directed adeno-associated virus (AAV) delivery of a functional MEF2C coding sequence during the juvenile period could modify disease-relevant phenotypes in mice heterozygous for a Mef2c exon 4 deletion. Transcript-level analysis identified a brain-enriched MEF2C isoform containing the α1 and β regions (nMEF2C) and a skeletal-muscle-enriched isoform containing α2 but lacking β (mMEF2C). Separate human-synapsin-driven AAV vectors encoding either isoform were administered at postnatal day 28. Control-treated Mef2c heterozygous mice retained baseline sociability but lacked social-novelty preference. Mice treated with either nMEF2C or mMEF2C displayed social-novelty preference and improved selected responses to a new social partner, whereas open-field effects were limited. nMEF2C replacement also corrected dark-phase wakefulness and non-rapid eye movement sleep abnormalities and modified selected state-dependent electroencephalographic ratios, without broadly changing absolute band amplitudes or social-contact electroencephalographic activity. Atlas-based whole-brain mapping revealed region-selective reductions in parvalbumin-immunoreactive profiles; direct statistical evidence of cellular rescue was confined to the secondary motor area after nMEF2C treatment. These findings show that selected MEF2C-dependent phenotypes remain modifiable during the juvenile period and support further optimization of MEF2C gene replacement with respect to isoform, dose, expression control, and cellular targeting.
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BibTeX
@misc{jiao2026juvenile,
title = {{Juvenile AAV-Mediated MEF2C Gene Replacement Ameliorates Selected Phenotypes in Mef2c-Haploinsufficient Mice}},
author = {Z. Jiao and C. Yu and T. Li and Y. Lai and Y. Yang and Y. Yuan and Y. Zhang and G. Tao and J. Wang and Z. Qiu},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.14.744746},
url = {https://www.biorxiv.org/content/10.64898/2026.08.14.744746v2},
note = {Public domain},
}
RIS
TY - UNPB
TI - Juvenile AAV-Mediated MEF2C Gene Replacement Ameliorates Selected Phenotypes in Mef2c-Haploinsufficient Mice
AU - Z. Jiao
AU - C. Yu
AU - T. Li
AU - Y. Lai
AU - Y. Yang
AU - Y. Yuan
AU - Y. Zhang
AU - G. Tao
AU - J. Wang
AU - Z. Qiu
PY - 2026
DA - 2026/08/14
PB - bioRxiv
DO - 10.64898/2026.08.14.744746
UR - https://www.biorxiv.org/content/10.64898/2026.08.14.744746v2
AB - MEF2C haploinsufficiency syndrome is a severe neurodevelopmental disorder for which no disease-directed treatment is available. We investigated whether neuron-directed adeno-associated virus (AAV) delivery of a functional MEF2C coding sequence during the juvenile period could modify disease-relevant phenotypes in mice heterozygous for a Mef2c exon 4 deletion. Transcript-level analysis identified a brain-enriched MEF2C isoform containing the α1 and β regions (nMEF2C) and a skeletal-muscle-enriched isoform containing α2 but lacking β (mMEF2C). Separate human-synapsin-driven AAV vectors encoding either isoform were administered at postnatal day 28. Control-treated Mef2c heterozygous mice retained baseline sociability but lacked social-novelty preference. Mice treated with either nMEF2C or mMEF2C displayed social-novelty preference and improved selected responses to a new social partner, whereas open-field effects were limited. nMEF2C replacement also corrected dark-phase wakefulness and non-rapid eye movement sleep abnormalities and modified selected state-dependent electroencephalographic ratios, without broadly changing absolute band amplitudes or social-contact electroencephalographic activity. Atlas-based whole-brain mapping revealed region-selective reductions in parvalbumin-immunoreactive profiles; direct statistical evidence of cellular rescue was confined to the secondary motor area after nMEF2C treatment. These findings show that selected MEF2C-dependent phenotypes remain modifiable during the juvenile period and support further optimization of MEF2C gene replacement with respect to isoform, dose, expression control, and cellular targeting.
ER -