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Lavrentovich and Hemkin (2008), Calcium Oscillations in Astrocytes

July 2009, model of the month by Michele Mattioni
Original model: BIOMD0000000184

The glia has always been seen as a "glue" wrapping around neurons, playing mainly a logistic and supporting role. Neurons, in contrast, are the cells able to transmit an electrical signal within the nervous system in a well-regulated manner.

However, experiments in situ [1] have shown interactions between neurons and astrocytes, one of the types of cells forming the glia. The capacity of astrocytes to influence the surrounding neuronal activity by releasing ATP [2] has raised the hypothesis that they may play a part in the regulation of signal transmission among neurons.

This activity can be associated with the concentration of Calcium, one of the most important cellular messengers, whose concentration in the astrocyte's cytosol is mainly influenced by external factors, although spontaneous oscillation have been observed.

Like Goto et al. had done earlier [3], Lavrentovich and Hemkin ([4], BIOMD0000000184) have proposed a model to investigate how spontaneous oscillations are triggered and sustained in the astrocytes. The model involves three variables: Ca2+ concentration in the cytosol, Ca2+ concentration in the Endoplasmic Reticulum and IP3 concentration in the whole cell. A schematic representation of the model is shown in Figure 1.

Schematic representation of the model.

Figure 1: Schematic representation of the model. Figure taken from [4].

The spontaneous perturbations of Ca2+ concentration are triggered by small changes in cytosolic Ca2+ concentration ([Ca2+]cyt), due to variations of flux across the cytosolic membrane.

Inositol cross-coupling and Calcium-induced release are the two mechanisms which sustain the oscillations. The main feedback loop involves the release of Ca2+ ions from the ER, modulated by IP3 and Calcium.

A small change in the cytosolic concentration of Calcium ions has two effects: PLC-gamma is triggered to convert the PIP2 into IP3, which is then able to cooperatively open the IP3 receptor and increase the cytosolic concentration of Calcium. The IP3 receptor also binds Calcium ions which activate opening at lower concentrations and have an inhibitory effect at higher concentrations.

The SERCA pump sequestrates Calcium ions from the cytosol and transfers them into the ER.

The typical oscillation (shown in Figure 2) produced by the model agrees with the experimental results obtained from epileptiform tissues, where the oscillation period is 100 s.

Typical oscillations produced by the model.

Figure 2: Typical oscillations produced by the model. Figure taken from [4].

Effect of IP3 receptor flow rate on oscillations.

Figure 3: Effect of the flow rate through IP3 receptors on Calcium oscillations. Wildtype: black line, reduced flow rate: red line. Figure taken from [4].

IP3 receptors play a key role in sustaining the oscillation. If the flow rate through these receptors is reduced or impaired, the oscillations are lost and the concentration of Calcium reaches a steady state, as shown in Figure 3.

This model shows how oscillations in the concentration of Calcium ions can be triggered and sustained without any external influences. A small change of the internal Calcium concentration is able to trigger the oscillation process, which is then self-sustained. This suggest a possible active role of the astrocytes in the signalling process, having the possibility to influence or modulate surrounding cells, and also playing a role in signal transmission within neurons.

Bibliographic References

  1. J. Kang, L. Jiang, S.A. Goldman, and M. Nedergaard. Astrocyte-mediated potentiation of inhibitory synaptic transmission. Nat Neurosci, 1:683-692, 1998. [SRS@EBI]
  2. A. Araque, V. Parpura, R.P. Sanzgiri, and P.G. Haydon. Glutamate-dependent astrocyte modulation of synaptic transmission between cultured hippocampal neurons. Eur J Neurosci, 10:2129-2142, 1998. [SRS@EBI]
  3. I. Goto, S. Kinoshita, K. Natsume. The model of glutamate-induced intracellular Ca2+ oscillation and intercellular Ca2+ wave in brain astrocytes. Neurocomputing, 58-60:461-467, 2004.
  4. M. Lavrentovich and S. Hemkin. A mathematical model of spontaneous calcium(II) oscillations in astrocytes. J Theor Biol, 251:553-560, 2008. [SRS@EBI]