glutamate release (Ni and Parpura, 2009; Parpura and Zorec, 2010), which in turn could increase GluR1 subunit phosphorylation by NMDA receptor-mediated activation of PKC (Fig. 5) (Malinow and Malenka, 2002). These pathways might both have contributed to the enhancement of hippocampal LTP that we observed in the human glial chimeras, although we found no evidence of enhancement of NMDA receptor activation after engraftment (Fig. 4C). Importantly, we found that thalidomide, a BBB-permeable inhibitor of TNFα, both diminished the enhancement of post-synaptic AMPA receptor current and reduced LTP in chimeric mice, yet had no such effects in unengrafted littermate controls. Behavioral analyses then revealed that human glial-chimeric mice exhibited improved learning and memory in four different tasks, including auditory and contextual fear conditioning, the Barnes Maze, and Object-Location Memory Task (Fig. 6). As with the chimerization-associated enhancement in LTP, the enhanced learning of chimeric mice in the object location recognition assay was eliminated by thalidomide treatment (Fig. 6D). Engraftment by neonatally delivered mouse GPCs enhanced neither LTP nor either auditory fear conditioning or Barnes maze performance, strongly suggesting that the potentiation of synaptic plasticity and learning afforded by glial progenitor cell chimerization was specific to human glia, and not a product
