Recruiting extrasynaptic NMDA receptors augments synaptic signaling.

N-Methyl-d-aspartate receptor (NMDAR) activation may promote cell survival or initiate cell death, with the outcome dependent on whether synaptic or extrasynaptic receptors are activated. Similarly, this differential activation has been proposed to govern the direction of plasticity. However, the physiological parameters necessary to activate extrasynaptic NMDARs in brain slices remain unknown. Using the irreversible use-dependent NMDAR antagonist MK-801 to isolate extrasynaptic NMDARs, we have tested the ability of short-stimulation trains from 5 to 400 Hz to activate these receptors on CA1 hippocampal slice pyramidal neurons. Frequencies as low as 25 Hz engage extrasynaptic NMDARs, with maximal activation at frequencies between 100 and 200 Hz. Since similar bursts of synaptic input occur during exploratory behavior in rats, our results demonstrate that "extrasynaptic" NMDARs regularly participate in synaptic transmission. Further, 175-Hz-stimulation trains activate all available synaptic and extrasynaptic dendritic NMDARs, suggesting these NMDARs act as synaptic receptors as needed, transiently increasing synaptic strength. Thus extrasynaptic NMDARs play a vital role in synaptic physiology, calling into question their status as "extrasynaptic."