title: A kinetic model of dopamine- and calcium-dependent striatal synaptic plasticity.
abstract: Corticostriatal synapse plasticity of medium spiny neurons is regulated by glutamate input from the cortex and dopamine input from the substantia nigra. While cortical stimulation alone results in long-term depression (LTD), the combination with dopamine switches LTD to long-term potentiation (LTP), which is known as dopamine-dependent plasticity. LTP is also induced by cortical stimulation in magnesium-free solution, which leads to massive calcium influx through NMDA-type receptors and is regarded as calcium-dependent plasticity. Signaling cascades in the corticostriatal spines are currently under investigation. However, because of the existence of multiple excitatory and inhibitory pathways with loops, the mechanisms regulating the two types of plasticity remain poorly understood. A signaling pathway model of spines that express D1-type dopamine receptors was constructed to analyze the dynamic mechanisms of dopamine- and calcium-dependent plasticity. The model incorporated all major signaling molecules, including dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP32), as well as AMPA receptor trafficking in the post-synaptic membrane. Simulations with dopamine and calcium inputs reproduced dopamine- and calcium-dependent plasticity. Further in silico experiments revealed that the positive feedback loop consisted of protein kinase A (PKA), protein phosphatase 2A (PP2A), and the phosphorylation site at threonine 75 of DARPP-32 (Thr75) served as the major switch for inducing LTD and LTP. Calcium input modulated this loop through the PP2B (phosphatase 2B)-CK1 (casein kinase 1)-Cdk5 (cyclin-dependent kinase 5)-Thr75 pathway and PP2A, whereas calcium and dopamine input activated the loop via PKA activation by cyclic AMP (cAMP). The positive feedback loop displayed robust bi-stable responses following changes in the reaction parameters. Increased basal dopamine levels disrupted this dopamine-dependent plasticity. The present model elucidated the mechanisms involved in bidirectional regulation of corticostriatal synapses and will allow for further exploration into causes and therapies for dysfunctions such as drug addiction.
authors.affiliation: Graduate School of Information Science, Nara Institute of Science and Technology, Ikoma, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Doi
authors.forename: Junichiro
authors.initials: J
authors.lastname: Yoshimoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Doya
mesh_terms: D001479:Basal Ganglia / Q000166:cytology / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D003198:Computer Simulation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D025461:Feedback, Physiological; D007700:Kinetics; D008959:Models, Neurological; D009473:Neuronal Plasticity / Q000502:physiology*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D054648:Protein Phosphatase 2; D002118:Calcium; D004298:Dopamine