However, when glutamate accumulates outside the synapse, it activates extrasynaptic NMDA receptors, which suppress CREB signaling and initiate neurotoxic cascades, in contrast to synaptic NMDA receptors that promote survival and plasticity (128, 129), This receptor-location-dependent signaling shift contributes to dendritic atrophy and functional decline observed in stress-related disorders such as depression. This evidence concerns the gene CREB1 and major depressive disorder.