TNFα regulates a number of cellular processes through protein kinase C (PKC)-mediated phosphorylation (Faurschou and Gniadecki, 2008), which is thus disrupted by thalidomide. Since phosphorylation of GluR1, at sites critical for its synaptic delivery, is both necessary and sufficient for lowering the threshold for inducing LTP (Hu et al., 2007), we thus next asked if the phosphorylation state of the GluR1 subunit differed between human glial chimeric mice and their littermate controls. We focused on two phosphorylation sites, Ser845 (PKA site) and Ser831 (PKC/CaMKII site), each of which is critical for the synaptic insertion of GluR1 (Hu et al., 2007), and assessed the effects upon each of human glial chimerization, and of thalidomide. Quantitative immunohistochemistry revealed that human glial chimeric mice exhibited a significant increase in Ser831 phosphorylation, the PKC-sensitive site (n=6; p=0.008, t-test); this was significantly attenuated in human glial chimeras receiving thalidomide, but not in their unengrafted control littermates (n=9-10; p>0.4, t test) (Fig. 5G). In contrast, phosphorylation of the Ser845 PKA site was unaffected by either the engraftment of human glia, or by thalidomide (n=6, p >
