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The Journal of Neuroscience, March 26, 2008, 28(13):3310-3323; doi:10.1523/JNEUROSCI.0303-08.2008

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Development/Plasticity/Repair
Requirement of an Allosteric Kinetics of NMDA Receptors for Spike Timing-Dependent Plasticity

Hidetoshi Urakubo,¹ Minoru Honda,² Robert C. Froemke,³ and Shinya Kuroda¹

¹CREST, Japan Science and Technology Agency, Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, ²Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa 277-8561, Japan, and ³Department of Molecular and Cellular Biology and Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720-3200

Correspondence should be addressed to either Hidetoshi Urakubo or Shinya Kuroda, Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. Email: urakubo{at}bi.s.u.-tokyo.ac.jp or Email: skuroda{at}bi.s.u-tokyo.ac.jp

Spike timing-dependent synaptic plasticity (STDP) plays an important role in neural development and information processing in the brain; however, the mechanism by which spike timing information is encoded into STDP remains unclear. Here, we show that a novel allosteric kinetics of NMDA receptors (NMDARs) is required for STDP. We developed a detailed biophysical model of STDP and found that the model required spike timing-dependent distinct suppression of NMDARs by Ca²⁺-calmodulin. This led us to predict an allosteric kinetics of NMDARs: a slow and rapid suppression of NMDARs by Ca²⁺-calmodulin with prespiking postspiking and postspiking prespiking, respectively. We found that the allosteric kinetics, but not the conventional kinetics, is consistent with specific features of amplitudes and peak time of NMDAR-mediated EPSPs in experiments. We found that the allosteric kinetics of NMDARs was also valid for synaptic plasticity induced by more complex spike trains in layer II/III of visual cortex. We extracted an essential synaptic learning rule by reduction of the allosteric STDP model and found that spike timing-dependent bidirectional role of postspiking in synaptic modification, which depends on the allosteric kinetics, is the essential principle in STDP. Thus, we propose a simple hypothesis of the allosteric kinetics of NMDARs that can coherently explain critical features of spike timing-dependent NMDAR-mediated EPSPs and synaptic plasticity.

Key words: LTP; LTD; spike timing-dependent plasticity; NMDA receptor; kinetic simulation; systems neurobiology

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Received Oct. 19, 2007; accepted Feb. 2, 2008.

Correspondence should be addressed to either Hidetoshi Urakubo or Shinya Kuroda, Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. Email: urakubo{at}bi.s.u.-tokyo.ac.jp or Email: skuroda{at}bi.s.u-tokyo.ac.jp

This article has been cited by other articles:

				K. E. Stephan, K. J. Friston, and C. D. Frith Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self-monitoring Schizophr Bull, May 1, 2009; 35(3): 509 - 527. [Abstract] [Full Text] [PDF]

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