FENS 2016, Copenhagen, Denmark July 2-6th 

Theme C. Disorders of the nervous system
Topic C16d. Mental disorders - Autism, mental retardation, and related disorders

Abstract title

Reduced inhibition and excitation underlies circuit-wide changes in vivo in a mouse model of Rett Syndrome

Balance of excitation and inhibition (E/I) plays a key role in refining neural circuit development and plasticity and is disrupted in many neurodevelopmental disorders. Rett syndrome (RTT) arises from loss of function mutations in Mecp2 in the brain. The functional effects of MeCP2 on synaptic E/I and circuit-level computations, and the role of MeCP2 in inhibitory neuron subtypes, are unresolved. Here, by analysing visual cortical responses using in vivo two-photon guided cell-attached and whole-cell patch-clamp recordings and awake Ca2+ imaging in MeCP2 mutant mice, we show that visually-evoked excitatory and inhibitory conductances are both reduced in pyramidal neurons. Deletion of MeCP2 from PV+ and SOM+ expressing inhibitory interneurons reduces their responses and selectivity. PV-specific deletion substantially recapitulates effects of global MeCP2 deletion, by differentially reducing response levels, reliability and selectivity of pyramidal neurons, and prolonging the window of cortical plasticity. Interestingly, Mecp2 deletion also results in defective KCC expression leading to chloride (Cl-) imbalance further impacting effectiveness of GABAergic inhibition. Administration of human recombinant IGF-1 cell-type specifically restores PV+ responses and increased KCC2 expression correcting polarity of GABAergic inhibition. Thus, loss of MeCP2 from specific interneuron types contributes crucially to the cell-specific and circuit-wide deficits of RTT, suggesting that such neurons have a pivotal role in the functional deficits that characterize the disorder. It also demonstrates a cell-type specific and mechanism-based therapeutic role for rhIGF1 in treating RTT.