Computational study of the role of calcium in late long-term potentiation induction on the basis of tripartite synapse structure

Abstract

In the present study, we propose a mathematical model to describe the key role of postsynaptic calcium concentration in Late Long-Term Potentiation (L-LTP) induction. This model is developed based on physiological facts of a typical CA3-CA1 tripartite synapse. In the proposed model, each astrocyte has a bidirectional signaling with pre synaptic neuron and based on its intracellular calcium oscillations sends signals to postsynaptic neuron. An increase in postsynaptic calcium concentration through NMDA receptor channels and voltage gated calcium channels (VGCC) activates calcium/calmodulin-dependent protein kinase II (CaMKII) auto-phosphorylation. When phosphorylated CaMKII concentration is high enough, conductance of AMPA receptors is intensified and postsynaptic neuron enhances subsequent presynaptic glutamate release through Nitric Oxide (NO) retrograde messenger. This mechanism leads to sustained increase in amplitude of excitatory post synaptic current (EPSC) known as L-LTP. Inasmuch as many studies have suggested that the cognitive decline seen in individuals with Alzheimer's disease (AD) may be resulted from impaired LTP, we investigated predictions of the proposed model in AD conditions. According to physiological evidence, we assumed that excessive accumulation of amyloid beta (Aβ) is the main cause of AD. Changes in calcium homeostasis, caused by decrease in NMDA receptor channels activity and increase in VGCC activity, disrupts the induction of L-LTP which is known as the major factor in memory loss in early stages of AD. This model presents the mechanism for increase in L-type VGCCs while NMDARs activity is reduced. According to the results of the present model, VGCCs activity is intensified due to 1) enhancement of presynaptic glutamate release, and 2) making postsynaptic membrane more depolarized, although, enhancement of glutamate release alone is not sufficient for LTP induction.