Similar to the RTT patient-derived neurons and RTT pathology previously described, WT neurons with MECP2 knockdown showed decreased spine density and soma size. RTT patient-derived neurons also exhibited functional alterations at the neural network level – a decrease in intracellular calcium oscillations and a decrease in frequency and amplitude of spontaneous post-synaptic excitatory currents compared to WT neurons 74,75. Calcium has wide-ranging effects in neurons ranging from microsecond level control of neurotransmitter secretion on the pre-synaptic side of the neurons to gene regulation in the neuron’s nucleus (which can last for hours or days). Calcium is also required for activity-dependent synaptic plasticity, a process crucial to learning and memory 76–79. The decrease of frequency and amplitude of spontaneous post-synaptic excitatory currents is consistent with the decrease in intracellular calcium transients and also indicates a decreased likelihood of action potential firing in the RTT patient-derived neurons. Note how these observations in RTT patient hiPSC-derived neurons would have been impossible to make in patients. From a translational perspective the Marchetto et al. study is also particularly promising as the group also showed rescue of certain neuron cell defects such as reduced VGLUT1 density with the administration of IGF-1 and/or gentamicin 74,75.
