Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Significance Understanding neurophysiological correlates of neurodevelopmental disorders is one of the pressing challenges of neuroscience. By analyzing a mouse model of Rett syndrome (RTT), we show that cortical pyramidal neurons in methyl-CpG binding protein 2 (MeCP2) mutant mice have reduced excitatory as well as inhibitory synaptic drive. Thus, neuronal response reliability and selectivity, features that arise from excitatory/inhibitory processing circuits within cortex, are reduced. MeCP2 deletion crucially regulates inhibition via two complementary mechanisms: reducing responses of parvalbumin-expressing (PV + ) inhibitory neurons and altering the polarity of GABAergic inhibition in pyramidal neurons. Treating mutant mice with recombinant human insulin-like growth factor-1 (rhIGF1) restores GABAergic polarity along with PV + and pyramidal neuron responses, thus providing a mechanistic basis of action of rhIGF1 in RTT.