One of the most challenging questions in neuroscience is to dissect how learning and memory, the foundational pillars of cognition, are grounded in stable, yet plastic, gene expression states. All known epigenetic mechanisms such as DNA methylation and hydroxymethylation, histone modifications, chromatin remodelling, and noncoding RNAs regulate brain gene expression, both during neurodevelopment and in the adult brain in processes related to cognition. On the other hand, alterations in the various components of the epigenetic machinery have been linked to well-known causes of intellectual disability disorders (IDDs). Two examples are Down Syndrome (DS) and Fragile X Syndrome (FXS), where global and local epigenetic alterations lead to impairments in synaptic plasticity, memory, and learning. Since epigenetic modifications are reversible, it is theoretically possible to use epigenetic drugs as cognitive enhancers for the treatment of IDDs. Epigenetic treatments act in a context specific manner, targeting different regions based on cell and state specific chromatin accessibility, facilitating the establishment of the lost balance. Here, we discuss epigenetic studies of IDDs, focusing on DS and FXS, and the use of epidrugs in combinatorial therapies for IDDs.

The research leading to the results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA Grant Agreement no. 608959. The work of the lab of M. Dierssen presented in the text is funded by FRAXA Foundation, Fondation Jerome Lejeune, Ministerio de Economia y Competitividad (SAF2013-49129-C2-1-R and “Centro de Excelencia Severo Ochoa 2013–2017,” SEV-2012-0208). The laboratory of M. Dierssen is supported by DIUE de la Generalitat de Catalunya (Grups consolidats SGR 2014/1125).