Rapid homeostatic downregulation of LTP by extrasynaptic GluN2B receptors

Although the activation of extrasynaptic GluN2B-containing NMDA receptors have been implicated in neurodegenerative diseases such as Alzheimer's and Hungtinton Disease, their physiological function remains unknown. In this study, we found that extrasynaptic GluN2B receptors play a homeostatic role by antagonizing LTP induction under conditions of prolonged synaptic stimulation. In particular, we have previously found that brief theta-pulse stimulation (5Hz for 30sec) triggers robust LTP whereas longer stimulation times (5Hz for 3min) have no effect on basal synaptic transmission in the hippocampal CA1 region. Here, we show that prolonged stimulation blocked LTP by activating extrasynaptic GluN2B receptors via glutamate spillover. In addition, we found that this homeostatic mechanism was absent in slices from the SAP102 knock-out providing evidence for a functional coupling between extrasynaptic GluN2B and the SAP102 scaffold protein. In conclusion, we uncovered a rapid homeostatic mechanism that antagonizes LTP induction via the activation of extrasynaptic GluN2B containing NMDA receptors.