Modeling signal transduction leading to synaptic plasticity: evaluation and comparison of five models

Abstract

An essential phenomenon of the functional brain is synaptic plasticity which is associated with changes in the strength of synapses between neurons. These changes are affected by both extracellular and intracellular mechanisms. For example, intracellular phosphorylation-dephosphorylation cycles have been shown to possess a special role in synaptic plasticity. We, here, provide the first computational comparison of models for synaptic plasticity by evaluating five models describing postsynaptic signal transduction networks. Our simulation results show that some of the models change their behavior completely due to varying total concentrations of protein kinase and phosphatase. Furthermore, the responses of the models vary when models are compared to each other. Based on our study, we conclude that there is a need for a general setup to objectively compare the models and an urgent demand for the minimum criteria that a computational model for synaptic plasticity needs to meet.

Figure 1

Schematic representation of the postsynaptic mechanisms involved in signal transduction related to induction of LTP/LTD. Intracellular calcium ions (Ca²⁺) bind to calmodulin (CaM), which further affects the activation of protein phosphatase 2B (PP2B) a.k.a. calcineurin (CaN), CaM-dependent kinase II (CaMKII), adenylyl cyclase (AC, the catalyst of the reaction producing cyclic adenosine monophosphate (cAMP)), and phosphodiesterase type 1B (PDE1B). Dopamine (DA) increases cAMP concentration via AC activation. Together with PDE1B, also PDE type 4 (PDE4) degrades cAMP. cAMP-dependent protein kinase (PKA) phosphorylates α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and protein phosphatase 1 (PP1) inhibitor 1 (I1). In addition, protein phosphatase 2A (PP2A) and cyclin-dependent kinase 5 (Cdk5) affect PP1 regulatory subunit a.k.a. DA- and cAMP-regulated neuronal phosphoprotein of 32 kDa (D32).

Figure 2

Four-train (a) calcium (Ca ²⁺ ) and (b) dopamine (DA) inputs used in simulations. 10 μM Ca²⁺ and 1 μM DA pulses are given for 1 s at time points , 503, 506, and 509 s. The duration of the basal plateau phases is thus 2 s. Before, between, and after the pulses a basal concentration of 0.1 μM for Ca²⁺ and 0.01 μM for DA is used.

Figure 3

Simulation results with different total concentrations of CaMKII and PP1. First column presents active CaMKII, second column PP1 (most models have only one unbound form of PP1), and third column the selected output of each model. (a)–(o) show 1200 s of simulation time.