The most parsimonious explanation for this result is that reducing

S6K1 levels nullifies the increased phosphorylation of translational control molecules such as S6 and eIF4B ( Figures 1 and 2) and exaggerated synthesis of proteins important for the expression of LTD. It previously was shown that expression of mGluR-LTD in hippocampal slices from S6K1 KO mice is blocked by anisomycin ( Antion et al., 2008a), whereas the enhanced mGluR-LTD in Fmr1 KO slices is anisomycin insensitive ( Nosyreva and Huber, 2006). It remains to be determined whether mGluR-LTD is protein synthesis dependent and whether activation of group I mGluRs triggers protein synthesis in the dKO mice. Afatinib purchase There have been conflicting reports of spine density changes in the hippocampus of Fmr1 KO mice that are likely due to differences in the techniques used and the age of the mice studied ( He and Portera-Cailliau, 2012). Our results showing increased spine density and morphology

phenotypes in CA1 pyramidal neurons from Fmr1 selleck inhibitor KO mice ( Figure 5) overlap with reports from other groups that examined mice more than 3 months of age ( Levenga et al., 2011). The correction of spine density and morphology phenotypes associated with FXS in the dKO mice suggests the possibility of an interaction of S6K1 with the Rac1/PAK pathway that has not been explored in neurons. Recently a role for S6K1 in Rac1-driven platelet activation and aggregation has been elucidated, consistent with this notion ( Aslan et al., 2011). first The regulation of Shank3

in dKO mice had added implications for spine morphology since this scaffolding protein has been shown to influence of spine remodeling via actin-dependent mechanisms ( Durand et al., 2012). Studies of the effects of S6K1 deletion have focused mainly on energy metabolism, caloric restriction, and insulin signaling ( Selman et al., 2009); there are few reports on the role of S6K1 in the nervous system. For example, the effects of deletion of S6K1 on neuronal morphology have not been reported. Consistent with their small stature, we observed a significant decrease in neuronal cell size ( Figure 2) and a trend for smaller dendritic arbors in S6K1 KO mice, although spine number and morphology were not different from those of WT mice ( Figure 5). We also found the enlarged testis phenotype to be overcorrected in the dKO mice ( Figure 7C), further supporting the idea that S6K1 is involved in the regulation of cellular size (both neuronal and nonneuronal) and spine morphology. The behavior of Fmr1 KO mice has been extensively studied and impairments in multiple socioemotional responses, hyperactivity, obsessive-repetitive behaviors, and susceptibility to seizures have been reported, many of which are consistent with ASD ( Gross et al., 2012; Spencer et al., 2011).