cAMP-dependent protein kinase mediates activity-regulated synaptic targeting of NMDA receptors

Chronic activity blockade increases synaptic levels of NMDA receptor immuno reactivity in hippocampal neurons. We show here that blockade-induced synap tic NMDA receptors are functional and mediate enhanced excitotoxicity in re sponse to synaptically released glutamate. Activity blockade increased the cell surface association of NMDA receptors. Blockade-induced synaptic targe ting of NMDA receptors did not require protein synthesis but required phosp horylation and specifically cAMP-dependent protein kinase (PKA). Furthermor e, activation of PKA was sufficient to induce synaptic targeting of NMDA re ceptors regardless of receptor activity status. These results implicate PKA activity downstream of receptor blockade as a mediator of enhanced synapti c transport or stabilization of NMDA receptors. Synaptic clustering of NR1- green fluorescent protein was observed in living neurons in response to NMD A receptor and cAMP phosphodiesterase antagonists and occurred gradually ov er the course of a day. This pathway represents a cellular mechanism for sy naptic homeostasis and is likely to function in metaplasticity, long-term r egulation of the ability of a synapse to undergo potentiation or depression .