, 2007 and Lei et al., 2010), NMDAR causes derepression of Kv4.2 production by inducing FMRP dephosphorylation to restore the Kv4.2 level within 20 min ( Figure 7), so as to terminate the positive feedback regulation mediated by Kv4.2 downregulation. Whereas chemical LTP causes Kv4.2 internalization and redistribution (Kim et al., 2007) and NMDAR activation causes PLX4032 significant reduction of Kv4.2 channels in a reversible manner (Lei et al., 2010), our finding of elevated Kv4.2 levels due to NMDA treatment in the presence of calpain inhibitors, taken together with the luciferase assay showing NMDAR-induced upregulation of translation associated with Kv4.2-3′UTR, strongly suggests that NMDAR

activation causes increased production of Kv4.2. Because new protein synthesis is clearly required for long-lasting XAV-939 in vitro activity-dependent changes in synaptic transmission, the manner by which neuronal activity engages the translational machinery is key to our understanding of long-term information storage. In addition to the rapid and bidirectional remodeling of synaptic NMDAR subunit composition by A-type K+ channel activity (Jung

et al., 2008), the activity-dependent regulation of Kv4.2 expression uncovered in our study provides a mechanism for rapid recovery of Kv4.2 after NMDAR-induced degradation. Whereas immediate downregulation of Kv4.2 upon NMDAR activation corresponds to positive feedback regulation important for synaptic plasticity, NMDAR-induced upregulation of Kv4.2 provides a means for negative feedback regulation for homeostasis. Both metabotropic and ionotropic glutamate receptors are known to regulate over local protein translation. With a requirement of local protein synthesis for mGluR-dependent LTP and LTD, mGluR activation rapidly increases

dendritic local protein synthesis (Sutton and Schuman, 2005). As to NMDAR-mediated translational regulation, NMDA treatment initially causes repression of overall protein synthesis (within 5 min), followed with preferential translation of specific targets such as CaMKIIα (Scheetz et al., 2000). In this study, we show that NMDAR signaling affects translation associated with Kv4.2-3′UTR and causes upregulation of Kv4.2 in an FMRP-dependent manner. Several studies have linked FMRP to NMDAR signaling, including dynamic dendritic FMRP localization in response to visual experience (Gabel et al., 2004a), accumulation of the mRNA encoding Arc/Arg3.1, a target of FMRP, in regions of activated synapses (Steward and Worley, 2001), and NMDA-induced total protein synthesis in synaptosomes (Muddashetty et al., 2007). We found that Kv4.2 upregulation by NMDAR is due to NMDAR-induced dephosphorylation of FMRP for de-repression of Kv4.2. It remains to be determined whether other transcripts besides Kv4.2 mRNA are regulated by NMDAR via the same signaling pathway. Dephosphorylation of FMRP may lead to the release of polysomes from the stalled state (Ceman et al., 2003).