Concurrently, DR from birth was able to preserve visual acuity into adulthood when measured behaviorally (Figure 2E) and supported by cortical VEP recording (Figure S1C). The improvement of cortical function was specific to V1, as motor performance on rotarod and open field behavioral assay remained impaired after DR (Figure S3A). To determine when sensory experience must be removed in order to prevent progressive loss of visual function, Mecp2 KO mice were deprived of input starting just before vision regressed. Visual acuity was first measured

behaviorally in a group of light-reared mutant mice at P30 (Figure 2D; p > 0.5 compared to WT littermates). A subset of these animals was then placed into total darkness, while the rest were kept in a normal light/dark cycle until adulthood (P55–60; Figure 2D). KO animals SB431542 nmr in the dark retained a significantly higher spatial acuity compared to light-reared littermates (p < 0.005). However, visual acuity was still at a lower level than that of WT light-reared mice at P60 (p < 0.005). We, therefore, placed Mecp2 KO mice in total darkness until P55–60 from earlier stages of postnatal development (just after eye opening at P14 or at P20). All rearing paradigms preserved visual acuity into adulthood, but only those mice placed in darkness from birth or immediately after eye opening showed visual acuity in the normal Hydroxychloroquine cost range of WT animals (Figure 2E; p > 0.05).

Taken together, these results surprisingly reveal that visual experience in

the absence of Mecp2 has a detrimental effect on visual cortical function. Taken together, our results support a developmental disruption of visual cortical circuits that precedes the loss of vision. We then examined when the PV hyperconnectivity first emerges in Mecp2 KO mice. Overall PV intensity and perisomatic Rolziracetam puncta (Figure 3A) were already significantly increased just after eye opening (P15) and well before the maturational trajectory for visual acuity deviates from normal. In contrast, decreased perisomatic GAD65 expression was not yet evident at P15 and only gradually appeared as the mice matured (>P30) (Figure 3A). To determine whether the early hyperconnectivity of PV puncta results in enhanced inhibitory function, we examined the spatial propagation of activity in visual cortical slices using VSDI (voltage-sensitive dye imaging; Grinvald and Hildesheim, 2004). We previously demonstrated that VSDI is sensitive to laminar changes in PV circuit reorganization (Lodato et al., 2011). Proper positioning and synaptogenesis of GABAergic cells is critical for maintaining signal propagation and E/I balance. PV circuits in particular potently gate the flow of thalamocortical activity through layer 4 (Cruikshank et al., 2007; Bagnall et al., 2011; Kirkwood and Bear, 1994; Rozas et al., 2001). We examined coronal visual cortical slices from KO and WT animals at P22–25, when PV circuits have normally reached maturity (Kuhlman et al.