Abstract

​Over the years, balance of excitation and inhibition (E/I) have provided a simplistic view of synaptic computation and its alteration in neurological disorders. Recent advances in understanding neural circuits that processes sensory information have revealed that even during normal physiological function, magnitude and direction of changes in excitation and inhibition is extremely dynamic to support ongoing circuit computation. In this talk, I will present evidences from Rett syndrome (RTT), a neurological disorder arising from loss of function mutations in Mecp2, how the functional effects of MeCP2 in inhibitory interneuron subtypes critically control visual information processing by non-cell autonomously affecting target cell response specificity and selectivity. Mecp2 deletion also alters cellular Cl- balance further impacting effectiveness of early inhibition. Administration of human recombinant IGF -1 (rhIGF1), a drug in Phase-II clinical trial, cell-type specifically restores cellular and circuit defects. Thus, loss of MeCP2 from specific interneuron types contributes crucially to the cell-specific and circuit-wide deficits in RTT , suggesting that targeting such neurons will offer a mechanism-based therapeutic role for rhIGF1 in treating RTT .​ ​Finally, I will discuss new approaches using awake behaving animals to study defects in learning dynamics in neurological disorders.