Prediction and validation of a mechanism to control the threshold for inhibitory synaptic plasticity.
Synaptic plasticity, neuronal activity-dependent sustained alteration of the efficacy of synaptic transmission, underlies learning and memory. Activation of positive-feedback signaling pathways by an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) has been implicated in synaptic plasticity. However, the mechanism that determines the [Ca(2+)](i) threshold for inducing synaptic plasticity is elusive. Here, we developed a kinetic simulation model of inhibitory synaptic plasticity in the cerebellum, and systematically analyzed the behavior of intricate molecular networks composed of protein kinases, phosphatases, etc. The simulation showed that Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), which is essential for the induction of synaptic plasticity, was persistently activated or suppressed in response to different combinations of stimuli. The sustained CaMKII activation depended on synergistic actions of two positive-feedback reactions, CaMKII autophosphorylation and CaMKII-mediated inhibition of a CaM-dependent phosphodiesterase, PDE1. The simulation predicted that PDE1-mediated feedforward inhibition of CaMKII predominantly controls the Ca(2+) threshold, which was confirmed by electrophysiological experiments in primary cerebellar cultures. Thus, combined application of simulation and experiments revealed that the Ca(2+) threshold for the cerebellar inhibitory synaptic plasticity is primarily determined by PDE1.
Kitagawa
Yuichi
Y
Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto, Japan.
Hirano
Tomoo
T
Kawaguchi
Shin-ya
SY
D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003198:Computer Simulation; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000378:metabolism; D025461:Feedback, Physiological; D008959:Models, Neurological; D009473:Neuronal Plasticity / Q000502:physiology*; D011689:Purkinje Cells / Q000378:metabolism / Q000502:physiology*; D015203:Reproducibility of Results; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D005680:gamma-Aminobutyric Acid; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D002118:Calcium