Relatively rapid homeostatic scaling up of synapses can also be evoked acutely by blocking NMDAR-mediated suppression of local protein translation. This increase in AMPAR-mediated current results from activation of local protein synthesis and increased availability of AMPAR subunits (Ju et al., 2004, Sutton et al., 2004 and Sutton et al., 2006). We found that protein translation-dependent scaling is occluded in the absence of GluN2B and is not rescued in 2B→2A neurons, suggesting that NMDAR-mediated suppression of protein translation is subunit specific.

From this we infer that a dominant role for GluN2B-containing NMDARs during development is to maintain appropriate levels of protein translation in dendrites in order to regulate synapse excitability. Consistent with this, we observed increased levels selleck inhibitor of phosphorylated S6K in dendrites lacking GluN2B and increased surface expression of AMPAR

subunits GluA1 and GluA2 in dendrites of GluN2B null neurons (Hall et al., 2007). mRNAs encode GluA1 and GluA2 traffic to dendrites, where their translation is locally regulated. Interestingly, antagonism of GluN2B-containing NMDARs results in upregulation of synaptic protein http://www.selleckchem.com/products/ulixertinib-bvd-523-vrt752271.html translation in vivo through activation of the mTOR pathway (Li et al., 2010). This suggests that it is through regulation of local protein synthesis that GluN2B antagonists may exert their effects as strong antidepressants (Maeng et al., 2008, Preskorn et al., 2008 and Li et al., 2010). It will be critically important to determine the exact molecular mechanism by which NMDARs, and specifically GluN2B, regulate protein synthesis in neuronal dendrites and to Carnitine dehydrogenase identify the RNA messages involved. Our experiments suggest that the specificity of GluN2B function is mediated through its preferential association with CaMKII. Regulation of AMPAR-mediated currents at developing cortical synapses requires CaMKII function downstream of GluN2B, because expression of a subunit mutant unable to

interact with CaMKII is ineffective at rescuing GluN2B loss of function. Importantly, although we observed that levels of activated (phosphorylated) CaMKII are depressed in the absence of GluN2B signaling, we actually observed an increase in the protein expression levels of this kinase and a decrease in the levels of beta CaMKII (data not shown). Interestingly, bidirectional homeostatic synaptic plasticity has been shown to involve reciprocal regulation of alpha and beta CaMKII (Thiagarajan et al., 2002 and Groth et al., 2011). Thus, it will be important in future studies to determine the exact conditions and mechanisms by which these enzymes are regulated by GluN2B and GluN2A-mediated signaling.