期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：E7287-E7296
DOI：10.1073/pnas.1615330113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceUnderstanding 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. Rett syndrome (RTT) arises from loss-of-function mutations in methyl-CpG binding protein 2 gene (Mecp2), but fundamental aspects of its physiological mechanisms are unresolved. Here, by whole-cell recording of synaptic responses in MeCP2 mutant mice in vivo, we show that visually driven excitatory and inhibitory conductances are both reduced in cortical pyramidal neurons. The excitation-to-inhibition (E/I) ratio is increased in amplitude and prolonged in time course. These changes predict circuit-wide reductions in response reliability and selectivity of pyramidal neurons to visual stimuli, as confirmed by two-photon imaging. Targeted recordings reveal that parvalbumin-expressing (PV+) interneurons in mutant mice have reduced responses. PV-specific MeCP2 deletion alone recapitulates effects of global MeCP2 deletion on cortical circuits, including reduced pyramidal neuron responses and reduced response reliability and selectivity. Furthermore, MeCP2 mutant mice show reduced expression of the cation-chloride cotransporter KCC2 (K+/Cl- exporter) and a reduced KCC2/NKCC1 (Na+/K+/Cl- importer) ratio. Perforated patch recordings demonstrate that the reversal potential for GABA is more depolarized in mutant mice, but is restored by application of the NKCC1 inhibitor bumetanide. Treatment with recombinant human insulin-like growth factor-1 restores responses of PV+ and pyramidal neurons and increases KCC2 expression to normalize the KCC2/NKCC1 ratio. Thus, loss of MeCP2 in the brain alters both excitation and inhibition in brain circuits via multiple mechanisms. Loss of MeCP2 from a specific interneuron subtype contributes crucially to the cell-specific and circuit-wide deficits of RTT. The joint restoration of inhibition and excitation in cortical circuits is pivotal for functionally correcting the disorder.
