It is well known that NMDA receptors (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 phosphoinositide 3-kinase (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.Here, we explored the role of an adaptor protein—adaptor protein containing pH domain, PTB domain, and leucine zipper motif (APPL1)—in this signal coupling using rat cortical neurons.