SNR was not significantly different between WT and c-KO littermates. Under these conditions, visual acuity was unaffected (Figure 4D). Our results establish an early derailment of PV circuit maturation in the total absence of Mecp2, which is manifest only later as a loss of visual acuity. We Bortezomib price next searched for a molecular correlate of the developmental rescue of PV-cells. It has been reported that NMDA receptor subunit 2A (Grin2a) and NR2B (Grin2b) transcription is misregulated in the absence of Mecp2 ( Asaka et al., 2006; Chahrour et al., 2008; Lee et al., 2008; McGraw et al.,

2011). Indeed, we identified Mecp2 binding to the Grin2a promoter in homogenates of visual cortex at P15 by ChIP-qPCR experiments ( Figure S4). Specifically, the DNA sequence Paclitaxel mw 3 kb upstream and 1 kb downstream of the TSS, revealed three CpG islands ( Figure S4 and Table S1; see Supplemental Experimental Procedures for details). We found that one of five unbiased primers (NR2A-1) exhibited statistically significant

binding of Mecp2 downstream of the Grin2a TSS (1.3 to 3.0 fold enrichment over IgG, p = 0.027; Figure S4 and Table S1). In contrast, binding of Mecp2 to the reported enrichment site for Grin2b ( Lee et al., 2008) was observed only in 3 out of 4 samples, therefore not meeting statistical significance ( Figure S4). In homogenates of Mecp2 KO mouse visual cortex, both NR2A and NR2B subunit expression were significantly decreased in adulthood (Table S2). However, NR2B disruption was more severe (Lee et al., 2008), resulting in

a significant increase of NR2A/2B ratio compared to adult WT mice (Figure 5A). A greater NR2B loss (−25%) with respect to NR2A (−13%) was already evident at P30 in V1 of the Mecp2 KO mice prior to regression of visual acuity (n = 3 mice each, WT versus KO, p < 0.05 t test). Together, our results support an early regulation of NR2A expression by Mecp2. Visual experience upon eye opening directly modulates NMDA receptor subunit composition in an activity-dependent manner (Quinlan et al., 1999). DR delays the switch from NR2B to 2A-enriched receptors (Figure 5A and Table S2). We found that DR of Mecp2 KO mice was sufficient to further downregulate Astemizole NR2A expression (Table S2), renormalizing NR2A/2B ratio to light-reared WT levels (Figure 5A). Moreover, selective disruption of NMDA receptors upon PV-cells in particular is known to alter cellular, network and behavioral function (Kinney et al., 2006; Belforte et al., 2010; Korotkova et al., 2010). We, therefore, examined whether direct NMDA receptor manipulation would yield a functional rescue in V1 similar to DR. To reestablish the proper NR2A/2B ratio in Mecp2 KO mice, either NR2B should increase or NR2A decrease. We focused on NR2A-deficient mice as a potential strategy for restoring NR2A/2B ratio and, consequently, vision in Mecp2 KO mice. NR2A KO mice are viable and healthy (Fagiolini et al.