Ionotropic NMDA receptor signaling is required for the induction of long-term depression in the mouse hippocampal CA1 region.
Previous studies have provided strong support for the notion that NMDAR-mediated increases in postsynaptic Ca(2+) have a crucial role in the induction of long-term depression (LTD). This view has recently been challenged, however, by findings suggesting that LTD induction is instead attributable to an ion channel-independent, metabotropic form of NMDAR signaling. Thus, to explore the role of ionotropic versus metabotropic NMDAR signaling in LTD, we examined the effects of varying extracellular Ca(2+) levels or blocking NMDAR channel ion fluxes with MK-801 on LTD and NMDAR signaling in the mouse hippocampal CA1 region. We find that the induction of LTD in the adult hippocampus is highly sensitive to extracellular Ca(2+) levels and that MK-801 blocks NMDAR-dependent LTD in the hippocampus of both adult and immature mice. Moreover, MK-801 inhibits NMDAR-mediated activation of p38-MAPK and dephosphorylation of AMPAR GluA1 subunits at sites implicated in LTD. Thus, our results indicate that the induction of LTD in the hippocampal CA1 region is dependent on ionotropic, rather than metabotropic, NMDAR signaling.
Department of Physiology, David Geffen School of Medicine, Interdepartmental Ph.D. Program for Neuroscience, Molecular, Cellular, and Integrative Physiology Ph.D. Program, and UCLA Integrative Center for Learning and Memory, University of California Los Angeles, Los Angeles, California 90095-1751, and Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California 94304.
Walter E
WE
Babiec
Ryan
R
Guglietta
Shekib A
SA
Jami
Wade
W
Morishita
Robert C
RC
Malenka
Thomas J
TJ
O'Dell
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D036881:Long-Term Synaptic Depression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002118:Calcium; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D048051:p38 Mitogen-Activated Protein Kinases
MK-801; NMDA receptor; hippocampus; long-term depression