Mechanisms of neurotransmitter driven depolarization in perisynaptic astrocytic processes
Ryo J. Nakatani*1and Erik De Schutter1
1Computational Neuroscience Unit, Okinawa Institute of Science and Technology, Okinawa, Japan
*Email: ryo.nakatani@oist.jp
Introduction
Electrophysiological properties of cells underlie the fundamental mechanisms of the brain. Although astrocytes have typically been considered not electrically excitable, recent studies show depolarization of astrocytes induced by local extracellular potassium changes [1]. Interestingly, astrocytic depolarization is induced within the periphery of cortical somatosensory astrocytes, proposed to be at contact sites between neurons and astrocytes. Astrocytic depolarization is thought to affect the brain’s information processing, as depolarization alters astrocyte neurotransmitter uptake [1, 2]. However, specific mechanisms causing astrocytic depolarization have yet to be confirmed due to the limitations of experimental techniques.
Methods Therefore, we aimed to construct a computational whole-cell astrocyte model to assess which channels were responsible for astrocyte depolarization. Our model included channels known to depolarize astrocytes, such as Kir 4.1, GLT-1 and GABAAR, and other channels we hypothesized to depolarize the astrocyte such as NMDAR (Fig. 1 top) [1, 3]. The model used a protoplasmic hippocampal astrocyte morphology [4], analogous to a cortical astrocyte, capturing both the soma and fine processes. Our model was also sensitive to extracellular ions, by simulating changes in reversal potential at different locations. This allowed us to create a simplified but accurate astrocyte model, responsive to neuronal activity. Results Our simulations show, depolarization by potassium uptake alone was unphysiological, requiring∼20 mM of potassium in physiological channel densities. However, the model reached experimentally observed 20 mV depolarizations in peripheral astrocytes by activating neurotransmitter receptors. Difference in neurotransmitter receptors created different decay dynamics, as well as difference in required channel densities to achieve experimental depolarization amplitudes. Depolarization in our model was mainly driven by the inward current from these receptors, which also induced small outward potassium currents and local increase in extracellular concentration (Fig. 1 bottom). All observed ion/potential changes were spatially confined.
Discussion
We hypothesize the strong attenuation, from high conductance and lack of voltage-dependent sodium channels, are key in isolating responses to local synapses. Moreover, our models show how both excitatory and inhibitory neurotransmitters can contribute to peripheral astrocytic depolarizations, revealing a possible mechanism of how astrocytes control synaptic efficacy through local increase of extracellular potassium (Fig. 1 bottom). Inter-synapse communication via astrocyte may also be possible, with inhibitory neurotransmitter induced depolarization altering diffusion dynamics in adjacent excitatory synapses. These insights suggest new mechanisms of how learning and memory are locally regulated by astrocytic processes.
Figure 1. Figure 1. Top: Schematic of whole-cell astrocyte computational model. Color scale show membrane potential during depolarization. Cartoon depicts channels in the computational model. Bottom: Voltage and currents recorded in PAP. (Left) A comparison of membrane potentials measured in sections marked within morphology. (Right) Individual currents recorded in the PAP for both GABAAR and NMDAR. Acknowledgements This research has been funded by OISTGU and by JSPS KAKENHI grant number 24KJ2184. References ● Armbruster, M. et al. (2022). Neuronal activity drives pathway-specific depolarization of peripheral astrocyte processes.Nature Neuroscience, 25(5). ● O’Kane, R. L. et al. (1999) Na+-dependent glutamate transporters of the blood-brain barrier: a mechanism for glutamate removal.Journal of Biological Chemistry, 274(45). ● MacVicar, B. A. et al. (1989) GABA-activated Cl-channels in astrocytes of hippocampal slices.Journal of Neuroscience, 9(10). ● Savtchenko, L. P. et al.(2018) Disentangling astroglial physiology with a realistic cell modelin silico.Nature communications, 9(1).
