Submitted on September 11, 2007
Accepted on October 31, 2007
Mechanisms Underlying De-depression of Synaptic NMDA Receptors in the Hippocampus
Wade Morishita1 and Robert C Malenka1*
1 Psychiatry, Stanford, Palo Alto, California, United States
* To whom correspondence should be addressed. E-mail: malenka{at}stanford.edu.
NMDA receptor (NMDAR)-mediated synaptic responses in hippocampal CA1 pyramidal cells are depressed during NMDAR-dependent long-term depression (LTD) due to mechanisms, in part, distinct from those underlying LTD of AMPA receptor (AMPAR)-mediated synaptic responses (Morishita et al. 2005). The mechanisms underlying de-depression of synaptic NMDARs, however, are not known. We find that de-depression of NMDAR-mediated synaptic responses in the CA1 region of the rat hippocampus is input-specific and does not require synaptic stimulation to be maintained. The induction of de-depression does not require activation of metabotropic glutamate receptors, L-type Ca2+ channels, release of Ca2+ from intracellular stores. It does, however, rely on activation of NMDARs. In contrast to the de-depression of AMPAR-mediated synaptic responses, de-depression of NMDAR-mediated synaptic responses does not depend on activation of calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), cAMP-dependent protein kinase (PKA) or Src kinases. However, de-depression of synaptic NMDARs is significantly impaired by inhibitors of mitogen-activated protein kinase (MAPK) signaling. Specifically, inhibitors of extracellular signal-regulated kinase 1/2(ERK1/2) prevented normal de-depression of synaptic NMDARs by a mechanism that did not require protein synthesis. These results provide further evidence that synaptic NMDARs can be bidirectionally modified by activity but via mechanisms distinct from those responsible for the activity-dependent, bidirectional modulation of synaptic AMPARs.
