The enhancement of LTP can result from both pre- and post-synaptic mechanisms. An analysis of paired-pulse facilitation before and after high frequency stimulation in chimeric mice suggested that post-synaptic mechanisms most likely underlie the enhancement of fEPSP slope in humanized chimeric mice (Figs. S3B-C). To evaluate the relative contribution of AMPA and NMDA receptor-mediated currents to the enhancement in LTP in the chimeric mice, we analyzed the effect of NMDA receptor blockade, using the NMDA receptor antagonist APV. We found that the NMDA receptor component accounted for only 4.7-12% of fEPSP, with no significant differences across the groups analyzed, indicating that NMDA NR1 expression was not increased in the human glial chimeras. These findings suggest that NMDA receptor activation played a minor role, if any, in the enhancement of synaptic plasticity in the chimeric mice (n=15-27) (Fig. 4C). Since NMDA receptors have a higher affinity for glutamate than do AMPA receptors (Malinow and Malenka, 2002), these observations also suggest that the potentiation of fEPSPs in human glial chimeric mice was not the result of increased synaptic release of glutamate; this is consistent with the lack of enhancement of paired-pulse suppression in the chimeric mice (Fig. S3B-C).
