People suffering from Huntington’s disease (HD) present cognitive deficits. Hippocampal dysfunction has been involved in the HD learning and memory impairment, but proteins leading this dysregulation are not fully characterized. Here, we studied the contribution of the family of transcription factors myocyte enhancer factor 2 (MEF2) to the HD cognitive deficits. To this aim, we first analyzed MEF2 protein levels and found that they are reduced in the hippocampus of exon-1 (R6/1) and full-length (Hdh^Q7/Q111) mutant huntingtin (mHTT) mice at the onset of cognitive dysfunction. By the analysis of MEF2 mRNA levels and mHTT-MEF2 interaction, we discarded that reduced MEF2 levels are due to changes in the transcription or sequestration in mHTT aggregates. Interestingly, we showed in R6/1 primary hippocampal cultures that reduction of MEF2 is strongly related to a basal and non-apoptotic caspase activity. To decipher the involvement of hippocampal decreased MEF2 in memory impairment, we used the BML-210 molecule that activates MEF2 transcriptional activity by the disruption MEF2–histone deacetylase class IIa interaction. BML-210 treatment increased the number and length of neurites in R6/1 primary hippocampal cultures. Importantly, this effect was prevented by transduction of lentiviral particles containing shRNA against MEF2. Then, we demonstrated that intraperitoneal administration of BML-210 (150 mg/Kg/day) for 4 days in R6/1 mice improved cognitive performance. Finally, we observed that BML-210 treatment also promoted the activation of MEF2-dependent memory-related genes and the increase of synaptic markers in the hippocampus of R6/1 mice. Our findings point out that reduced hippocampal MEF2 is an important mediator of cognitive dysfunction in HD and suggest that MEF2 slight basal activation could be a good therapeutic option.

患有亨廷顿舞蹈病（HD）的人存在认知缺陷。海马功能障碍已参与高清学习和记忆障碍，但导致这种功能失调的蛋白质尚未完全表征。在这里，我们研究了转录因子家族肌细胞增强因子2（MEF2）对HD认知缺陷的贡献。为此，我们首先分析了MEF2蛋白水平，发现它们在外显子1（R6 / 1）和全长（Hdh ^{Q7 / Q111}）的海马中均降低）认知功能障碍发作的亨廷顿（mHTT）突变小鼠。通过对MEF2 mRNA水平和mHTT-MEF2相互作用的分析，我们放弃了降低的MEF2水平是由于mHTT聚集体中转录或螯合变化的缘故。有趣的是，我们在R6 / 1原代海马培养物中显示，MEF2的减少与基础和非凋亡的半胱天冬酶活性密切相关。为了破译海马减少的MEF2参与记忆障碍，我们使用了BML-210分子，该分子通过破坏MEF2-组蛋白去乙酰化酶IIa类相互作用来激活MEF2转录活性。BML-210处理增加了R6 / 1原代海马培养物中神经突的数量和长度。重要的是，可以通过转导含有针对MEF2的shRNA的慢病毒颗粒来防止这种效应。然后，我们证明了在R6 / 1小鼠中腹腔注射BML-210（150 mg / Kg /天）4天可以改善认知能力。最后，我们观察到BML-210处理还促进了R6 / 1小鼠海马中依赖MEF2的记忆相关基因的激活和突触标记的增加。我们的研究结果表明，海马MEF2减少是HD认知功能障碍的重要介体，并提示MEF2轻微的基础激活可能是一个好的治疗选择。