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.

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

“…Nakano et al specifically explored the contribution of dopamine signaling to AMPAR trafficking in striatal neurons (18). Although the Nakano computational model contained the core signaling steps of dopamine-mediated AMPAR insertion, it did not agree with our experimental data.…”

“…Previous models of dopamine signaling have highlighted the importance of a positive feedback loop between PKA, PP1, and DARPP-32/I1 on AMPAR trafficking (18,20). In this study, we propose a unique regulatory motif involving ERK-mediated regulation of PDE4, resulting in an increase in the activation of PKA and its downstream effectors.…”

“…Several computational models have explored the underlying signaling that controls AMPAR trafficking (16)(17)(18)(19)(20). Nakano et al specifically explored the contribution of dopamine signaling to AMPAR trafficking in striatal neurons (18).…”

A neuroeconomic theory of bidirectional synaptic plasticity and addiction

“…Mathematically speaking, the BCM theory is expressed as: . It is further to be noted that synaptic plasticity is known to be related to the ratio of NMDA/AMPA receptor expressions at the postsynaptic neurons [10] and an increased proportion of NR2B-containing NMDA receptors at silent synapses in the nucleus accumbens [11].…”

Magnesium in the Central Nervous System

“…There is a growing body of evidence that Mg plays an important role in synaptic plasticity and is involved in long--term potentiation (LTP) and long--term depression (LTD) of synaptic transmission . LTP is induced by cortical stimulation in Mg--free solutions and it is associated with massive calcium influx through NMDA--type receptors (Nakano et al, 2010). Diamond et al, (2007) suggested that complex interactions between LTP and LTD processes in the hippocampus contribute to the storage of emotional memories and stress--induced amnesia.…”