Ionotropic NMDA Receptor Signaling Is Required for the Induction of Long-Term Depression in the Mouse Hippocampal CA1 Region
- Walter E. Babiec1,*,
- Ryan Guglietta2,*,
- Shekib A. Jami3,
- Wade Morishita5,
- Robert C. Malenka5, and
- Thomas J. O'Dell1,4
- 1Department of Physiology, David Geffen School of Medicine,
- 2Interdepartmental Ph.D. Program for Neuroscience,
- 3Molecular, Cellular, and Integrative Physiology Ph.D. Program, and
- 4UCLA Integrative Center for Learning and Memory, University of California Los Angeles, Los Angeles, California 90095-1751, and
- 5Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, California 94304
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Author contributions: W.E.B., R.G., S.A.J., W.M., R.C.M., and T.J.O. designed research; W.E.B., R.G., S.A.J., W.M., and T.J.O. performed research; W.E.B., R.G., S.A.J., W.M., and T.J.O. analyzed data; W.E.B., R.M., and T.J.O. wrote the paper.
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↵*W.E.B. and R.G. contributed equally to this work.
Abstract
Previous studies have provided strong support for the notion that NMDAR-mediated increases in postsynaptic Ca2+ 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 Ca2+ 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 Ca2+ 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.
- Received December 28, 2013.
- Revision received March 4, 2014.
- Accepted March 7, 2014.
- Copyright © 2014 the authors 0270-6474/14/345285-06$15.00/0
