Previous studies have analyzed the effect of TNFα on excitatory transmission in vitro, by adding soluble TNFR1 receptors to scavenge free TNFα (Beattie et al., 2002; Stellwagen and Malenka, 2006). Since soluble TNFR1 would not be expected to be an efficient inhibitor in vivo, we instead administered thalidomide, a potent, BBB permeable inhibitor of TNFα production (Ryu and McLarnon, 2008). Human glial chimeric mice treated with thalidomide exhibited a significant suppression of fEPSP slopes compared to those receiving vehicle (0.5% carboxy-methylcellulose) (1.41 ± 0.15 mV/ms vs. 1.05 ± 0.24 mV/ms at 0.1mA; means ± SEM; p<0.05, n = 12). In contrast, excitatory transmission in unengrafted littermates was unaffected by thalidomide (1.02 ± 0.12 mV/ms vs. 0.97 ± 0.20 mV/ms at 0.1mA; p=0.32, n =12). These observations suggested that thalidomide selectively targeted the potentiation of excitatory transmission mediated by human glial TNFα. Accordingly, thalidomide also reduced the expression of both TNFα and GluR1 in the human glial chimeras, but not that of NR1 (Fig. 5D). Importantly, thalidomide also prevented the facilitation of LTP in the human glial chimeras: Two trains of
