Altered neuronal network and rescue in a human MECP2 duplication model

Abstract

Increased dosage of MeCP2 results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSC) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increase synaptogenesis and dendritic complexity. Additionally, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 function at the epigenetic level, we tested if these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders.

Further delineation of theMECP2duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

“…It has also been shown that increased MeCP2 dosage in mice leads to increased synaptic numbers, having therefore a major impact on the formation of excitatory synapses 19. In the same way, it has been elegantly demonstrated that cortical neurons derived from different induced pluripotent stem cells (iPSC) lines of patients with MECP2 duplication syndrome have increased synaptogenesis and dendritic complexity and that their neuronal network synchronisation was altered 20. These findings contribute to the understanding of the underlying pathways that lead to the very severe neurodevelopmental phenotype of this disease.…”

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops

“…Current high-water marks of thinking in the field are represented by the following categories of papers, each with both value and limitation: Research publications that focus on a mouse model of monogenic ASD, often followed up by attempted amelioration of ASD-like behavior with pharmacological intervention (Aguilar-Valles et al, 2015; Bear et al, 2004; Braat et al, 2015; Chevere-Torres et al, 2012; Choi et al, 2011; Gkogkas et al, 2014; Nageshappa et al, 2015). This approach admirably takes direct aim at issues of necessity and sufficiency, but by definition is only credible for a subset of ASD, even when the scope is broadened by considering the pathways that may be affected (Mullard, 2015).…”

Modeling autism spectrum disorders with human neurons

“…In our study, RTT neurons had fewer synapses, reduced spine density, smaller soma size, altered calcium signaling, and electrophysiological defects when compared to controls (Marchetto et al, 2010). Interestingly, when modeling MECP2 duplication syndrome, we found neuronal phenotypes that go in opposite direction of what was observed in RTT-derived neurons (Nageshappa et al, 2015). This observation suggests that MeCP2 levels in human neurons must be tightly controlled.…”