Juvenile AAV-Mediated MEF2C Gene Replacement Ameliorates Selected Phenotypes in Mef2c-Haploinsufficient Mice

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 1 and {beta} regions (nMEF2C) and a skeletal-muscle-enriched isoform containing 2 but lacking {beta} (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.