It is well known that NMDARs can both induce neurotoxicity and promote neuronal survival under different circumstances.Recent studies show that such paradoxical responses are related to the receptor location: the former to the extrasynaptic and the latter to the synaptic.The PI3K/Akt kinase cascade is a key pathway responsible for the synaptic NMDAR-dependent neuroprotection.However, it is still unknown how synaptic NMDARs are coupled with the PI3K/Akt pathway.In this study, we found that an adaptor protein,APPL1 (adaptor protein containing pH domain, PTB domain, and leucine zipper motif),existed in post-synaptic densities and associated with the NMDAR complex through binding to PSD95 at its C-terminal PDZ-binding motif.NMDARs, APPL1 and the PI3K/Akt cascade formed a complex in cortical neurons.Synaptic NMDAR activity increased the association of this complex, induced activation of the PI3K/Akt pathway, and consequently protected neurons against starvation-induced apoptosis.Perturbing APPL1 interaction with PSD95 by a peptide comprising the APPL1 C-terminal PDZ-binding motif dissociated the PI3K/Akt pathway from NMDARs.Either the peptide or lentiviral knock-down of APPL1 blocked synaptic NMDAR-dependent activation of Akt and synaptic NMDAR-dependent neuroprotection.These results suggest that APPL1 contributes to connecting synaptic NMDARs with the intracellular PI3K/Akt cascade and the downstream pro-survival signaling pathway.