The article discusses the contrasting roles of synaptic and extrasynaptic N-methyl-D-aspartate receptors (NMDARs) in neuronal health and dysfunction. Synaptic NMDARs promote neuroprotection by enhancing nuclear Ca²⁺ signaling, which activates transcription factors like CREB and targets genes that enhance mitochondrial health, antioxidant defenses, and suppress apoptosis. In contrast, extrasynaptic NMDARs promote cell death through various pathways, including CREB dephosphorylation, ERK1/2 inactivation, FOXO activation, calpain activation, and STEP cleavage. The balance between synaptic and extrasynaptic NMDAR activity is crucial in conditions like acute ischemia and Huntington's disease, where an imbalance can lead to neuronal dysfunction and death. Therapeutic strategies should aim to enhance synaptic NMDAR activity while disrupting extrasynaptic NMDAR-dependent death signaling, such as using memantine, a well-tolerated NMDAR antagonist that preferentially blocks chronic extrasynaptic NMDAR activity.The article discusses the contrasting roles of synaptic and extrasynaptic N-methyl-D-aspartate receptors (NMDARs) in neuronal health and dysfunction. Synaptic NMDARs promote neuroprotection by enhancing nuclear Ca²⁺ signaling, which activates transcription factors like CREB and targets genes that enhance mitochondrial health, antioxidant defenses, and suppress apoptosis. In contrast, extrasynaptic NMDARs promote cell death through various pathways, including CREB dephosphorylation, ERK1/2 inactivation, FOXO activation, calpain activation, and STEP cleavage. The balance between synaptic and extrasynaptic NMDAR activity is crucial in conditions like acute ischemia and Huntington's disease, where an imbalance can lead to neuronal dysfunction and death. Therapeutic strategies should aim to enhance synaptic NMDAR activity while disrupting extrasynaptic NMDAR-dependent death signaling, such as using memantine, a well-tolerated NMDAR antagonist that preferentially blocks chronic extrasynaptic NMDAR activity.