, 2011), enabling continuous mGlu5 inhibition with a receptor occupancy of ca. 81% ± 4% (Figure 1). Acute treatment with CTEP rescued elevated protein synthesis in hippocampal slices, and single-dose administration in vivo normalized LTD ex vivo and suppressed the audiogenic seizure phenotype. Four weeks of chronic CTEP treatment starting at the age of 5 weeks reversed the learning and memory deficit in the inhibitory avoidance test (Figure 2), the hypersensitivity to auditory stimuli, the increased dendritic spine density in the primary visual cortex (Figure 3), and the elevated ERK and mTOR activities in the cortex of

Fmr1 KO mice. Chronic CTEP treatment for 17 weeks also corrected elevated locomotor activity ( Figures 2H and 2I) and partially

reversed macroorchidism PCI-32765 order ( Figure 3J) without affecting testosterone and progesterone plasma levels ( Figures 3K and 3L). For some measures (e.g., elevated protein synthesis, auditory hypersensitivity, basal dendrite spine density, and ERK phosphorylation), the corrective effects of CTEP were specific for Fmr1 KO mice, whereas for others (e.g., LTD, inhibitory avoidance, and locomotor activity) CTEP treatment also had a proportional effect on WT mice. Regardless, CTEP treatment moved fragile X phenotypes closer to the ZD1839 purchase untreated WT situation for all these measures. The important and therapeutically relevant conclusion is that a broad spectrum of FXS phenotypes—biochemical, structural, and behavioral—can be improved with treatment onset in early adulthood in mammals. Our results are in good agreement with the comprehensive phenotypic rescue obtained by genetic reduction of mGlu5 expression levels (Dölen et al., 2007). A limitation of the genetic approach, however, was that mGlu5 expression levels were reduced at the earliest stage of embryonic development and thus may prevent the development of phenotypes rather than correct them. With respect to pharmacological mGlu5 inhibition, a study by Su et al. (2011)

reported during a rescue of increased dendritic spine density in cortical neurons in vivo by 2 weeks of MPEP administration when treatment started at birth, but not when treatment started in 6-week-old animals. All other experiments reporting correction of the increased spine density phenotype with mGlu5 antagonists (MPEP, fenobam, and AFQ056) were limited to in vitro experiments on primary cultured neurons (de Vrij et al., 2008 and Levenga et al., 2011). In contrast to the results of Su et al. (2011), our data show that starting treatment immediately after birth is not a requirement; instead, chronic treatment starting in young adulthood can reverse an established phenotype.