1 mRNA in dendrites (Raab-Graham et al., 2006), voltage-gated ion channels now join the rank of postsynaptic scaffolding proteins such as PSD-95 and SAPAPs, activity-dependent synaptic proteins such as CaMKIIα, Arc, and MAP1b, and ligand-activated ion channels such as GluR1/2 and GABAARδ (Bassell and Warren, 2008) as dendritic proteins with their mRNAs localized in neuronal dendrites and under the regulation of synaptic activity. FXS, the most common heritable mental retardation often associated with

autism, is caused by the loss of FMRP function click here (Bagni and Greenough, 2005). Our finding of Kv4.2 mRNA association with FMRP in neuronal dendrites and direct binding of FMRP to Kv4.2-3′UTR led us to discover that Kv4.2 is under

the control of FMRP. Whereas loss of FMRP resulted in no significant changes in Kv4.2 mRNA level or dendritic localization, it caused a dramatic increase of total Kv4.2 levels in the CA1 dendritic field FG-4592 price of the hippocampus and in cultured hippocampal neurons from fmr1 KO mice. Similar elevation of Kv4.2 levels was also found for surface expression of Kv4.2, especially on distal dendrites, revealing FMRP suppression of Kv4.2 in vivo. Whereas we found elevated Kv4.2 in the hippocampal dendritic field of 3-week-old as well as 2-month-old fmr1 KO mice ( Figure 5A), a recent study reports Kv4.2 levels are reduced in fmr1 KO mice ( Gross et al., 2011), however, this conclusion is PAK6 based on Kv4.2 immunostaining that shows a different pattern from the documented Kv4.2 expression in stratum radiatum but low in stratum lacunosum moleculare ( Menegola and Trimmer, 2006) thus raising question about the specificity of the immunostaining. This study also reports that GFP-Kv4.2 3′ UTR is associated with mCherry-FMRP but not mCherry-RGG or other FMRP fragments that contain one or both RNA-binding domains ( Gross et al., 2011). In contrast, we found direct binding of Kv4.2 3′UTR to FMRP as well as its RGG-containing C-terminal domain ( Figures 3E–3G). Not only is FMRP required for suppression of dendritic Kv4.2, it is also essential for NMDAR-induced Kv4.2 protein production that enables Kv4.2

level to fully recover after its degradation and downregulation induced by NMDAR activation. FMRP thus plays a crucial role in tuning the dendritic Kv4.2 channel density and permitting dynamic regulation of Kv4.2 during synaptic activities. We found the elevated Kv4.2 level in fmr1 KO mice contributes to the LTP deficits ( Lauterborn et al., 2007), because the Kv4 channel blocker HpTx2 dose-dependently restored LTP induction by five theta bursts ( Figure 6). Given that hippocampal CA1 neurons lacking FMRP can exhibit LTP in response to strong stimuli (ten theta bursts) ( Lauterborn et al., 2007), Kv4.2 suppression by FMRP appears to be important for maintaining these neurons within the dynamic range for synaptic plasticity. Moreover, concurrent with NMDAR-induced Kv4.