Requirement of an allosteric kinetics of NMDA receptors for spike timing-dependent plasticity.
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 Ca(2+)-calmodulin. This led us to predict an allosteric kinetics of NMDARs: a slow and rapid suppression of NMDARs by Ca(2+)-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.
Urakubo
Hidetoshi
H
CREST, Japan Science and Technology Agency, Department of Biophysics and Biochemistry, Graduate School of Science, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. urakubo@bi.s.u.-tokyo.ac.jp
Honda
Minoru
M
Froemke
Robert C
RC
Kuroda
Shinya
S
D000200:Action Potentials / Q000502:physiology*; D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists; D066298:In Vitro Techniques; D008959:Models, Neurological; D009415:Nerve Net; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013569:Synapses; D009435:Synaptic Transmission; D013997:Time Factors; D014793:Visual Cortex / Q000166:cytology
D002147:Calmodulin; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium