Pharmacological reversal of synaptic and network pathology in human MECP2‐KO neurons and cortical organoids

Trujillo CA, Adams JW, Negraes PD, Carromeu C, Tejwani L, Acab A, Tsuda B, Thomas CA, Sodhi N, Fichter KM, Romero S, Zanella F, Sejnowski TJ, Ulrich H, Muotri AR.

EMBO Molecular Medicine, 2020



One known cause of neurodevelopmental impairment, in particular Rett syndrome, is duplication or deficiency of the MECP2 gene. Human stem cell-derived neurons and cortical organoids provide a platform to understand the mutation and develop therapies, including pharmacological treatments.  The authors found that two compounds were able to reverse the neuropathologic phenotypes in hiPSC-derived models with the MECP2 gene mutation.


Data recorded on Maestro MEA system

The authors tested the effects of Nefiracetam, PHA 543613, and Acamprosate on synaptic function and network activity with calcium imaging and microelectrode array (MEA) technologies.  The electrophysiological activity showed a decrease in percentage of active neurons and a decrease in spike frequency.  Dosing with Nefiracetam and PHA 543613 restored the spike frequency in MECP2-KO neurons.

One month old cortical neurons were plated on MEA plates and recorded with the Neural software module.  Axion's Neural Metric Tool was used to classify the organoids as "active".  Spike and burst analysis was analyzed from the recordings.  Nefiracetam and PHA 543613 increased the MEA network activity of MECP2-KO cortical organoids, however did not show a full restoration of activity.