Mark Neznansky: Computational Modelling of Calcium-Buffering Proteins in Astrocytes

BCCN Berlin/TU Berlin

Astrocytes, one of the several cell types composing the group of “neuroglia” in the CNS, started getting attention from the scientific community much later than neurons, and their understanding still lags behind. On the cell morphology level, the astrocytes of humans distinct themselves from those of other organisms, including other mammals, to a much greater degree than their neurons which are strongly preserved between species. This alludes to a potential role in engendering the unique mental faculties of Homo sapiens, and given their pivotal role in some neurological disorders such as Alzheimer’s disease, their research has much merit.
Unlike neurons that use an electric signal, but like many other cells, astrocyte employ calcium signal whereby the concentration of Ca2+ inside the cell is manipulated. Therefore the monitoring of their state is very different in nature; one can measure the membrane potential of neurons to get the state of their excitation, but one must introduce calcium indicators in order to measure Ca2+. The disadvantage here is that by binding calcium, this method alters the signal as it measures it.
There have been many experimental and computational models that investigated the effects of Ca2+ binding molecules—“calcium buffers”—including some studies that looked specifically on their effect in astrocytic systems. However, there hasn’t been much research that looked at the explicit interaction of buffers with Ca2+ in a model that simulated an astrocyte.
In the present thesis we took a detailed point model of the mGluR pathway in astrocytes which is capable of generating the Ca2+- oscillations that characterize calcium signaling, and augmented it by introducing calcium buffers. We investigated the effects of different parameter values on the calcium signal for astrocytes employing two encoding schemes — amplitude and frequency modulations. We found that buffering affects the oscillation frequencies and amplitudes of FM and AM astrocytes, respectively, and that a combination of strong buffering and strong stimulus might lead the cell to have static toxic levels of Ca2+. Further, we found that while mostly buffering had an intuitive effect on the Ca2+ signal, it also possesses a bifurcation-parameter like properties, in the sense that its variation can lead to qualitative changes in the signal. The role of spatiality in astrocyte models, the often cited claim that 99% of Ca2+ in cells is buffered and the potential non-trivial effect of having more than one buffer type, are discussed.

Additional Information

Master thesis defense in the International Master Program Computational Neuroscience.

Organized by

Klaus Obermayer / Robert Martin

Location

BCCN Berlin, lecture hall, Philippstr. 13 Haus 6, 10115 Berlin