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 HFS failed to trigger LTP in slices taken from chimeras pre-treated with thalidomide (106.3 ± 3.9%, n=6, 12.6 ± 0.3 months of age), whereas the activity-dependent potentiation of fEPSPs persisted in vehicle-treated human glial chimeras (117.6 ± 4.8 %, n=6, 12.5 ± 0.5 months; p<0.05, t test) (Fig. 5E). Thalidomide did not alter the number of NMDA receptors activated in response to medial perforant-path fiber stimulation in either chimeric or unengrafted controls, suggesting that thalidomide specifically suppressed the number of functional AMPA receptors consistent with prior publications showing that TNFα drives membrane insertion of AMPA receptors (Fig. 5F) (Beattie et al., 2002; Stellwagen and Malenka, 2006). Thus, TNFα released by human glial cells (Fig. S4A, Fig. 5C) enhanced host neuronal fEPSPs by increasing the number of functional postsynaptic GluR1 AMPA receptors (Fig. 5C), and conversely, thalidomide suppressed plasma membrane insertion of AMPA, but not NMDA receptors by inhibiting TNFα production (Fig. 5D).
