Astrocytic Ion Dynamics: Implications for Potassium Buffering and Liquid Flow

We review modeling of astrocyte ion dynamics with a specific focus on the implications of so-called spatial potassium buffering, where excess potassium in the extracellular space (ECS) is transported away to prevent pathological neural spiking. The recently introduced Kirchoff-Nernst-Planck (KNP) scheme for modeling ion dynamics in astrocytes (and brain tissue in general) is outlined and used to study such spatial buffering. We next describe how the ion dynamics of astrocytes may regulate microscopic liquid flow by osmotic effects and how such microscopic flow can be linked to whole-brain macroscopic flow. We thus include the key elements in a putative multiscale theory with astrocytes linking neural activity on a microscopic scale to macroscopic fluid flow.Comment: 27 pages, 7 figure

Mammalian Brain As a Network of Networks

Acknowledgements AZ, SG and AL acknowledge support from the Russian Science Foundation (16-12-00077). Authors thank T. Kuznetsova for Fig. 6.Peer reviewedPublisher PD

Computational Astrocyence: Astrocytes encode inhibitory activity into the frequency and spatial extent of their calcium elevations

Deciphering the complex interactions between neurotransmission and astrocytic $Ca^{2+}$ elevations is a target promising a comprehensive understanding of brain function. While the astrocytic response to excitatory synaptic activity has been extensively studied, how inhibitory activity results to intracellular $Ca^{2+}$ waves remains elusive. In this study, we developed a compartmental astrocytic model that exhibits distinct levels of responsiveness to inhibitory activity. Our model suggested that the astrocytic coverage of inhibitory terminals defines the spatial and temporal scale of their $Ca^{2+}$ elevations. Understanding the interplay between the synaptic pathways and the astrocytic responses will help us identify how astrocytes work independently and cooperatively with neurons, in health and disease.Comment: 4 pages, 3 figures, IEEE-EMBS International Conference on Biomedical and Health Informatics (BHI '19

A computational study of astrocytic glutamate influence on post-synaptic neuronal excitability

<p><b>Postsynaptic activity due to synaptic and intrinsic currents</b>, triggered by (a) synaptic glutamate [Glu]_syn (b-d) simulation with [Glu]_ast,eq = 1.5mM, 5mM, and 10mM respectively, synaptic currents (I_syn) combined AMPA- and NMDA-mediated currents in response to synaptic glutamate, membrane potential (V_m) of postsynaptic neuron resulting from combination of I_syn and voltage-gated currents (Na⁺, K⁺ and leak). Prolonged time course of synaptic glutamate leads to enhanced synaptic currents (I_syn) and higher frequency postsynaptic firing response (V_m depolarisations) as [Glu]_ast,eq increases.</p

GABA Regulation of Burst Firing in Hippocampal Astrocyte Neural Circuit: A Biophysical Model

It is now widely accepted that glia cells and gamma-aminobutyric acidergic (GABA) interneurons dynamically regulate synaptic transmission and neuronal activity in time and space. This paper presents a biophysical model that captures the interaction between an astrocyte cell, a GABA interneuron and pre/postsynaptic neurons. Specifically, GABA released from a GABA interneuron triggers in astrocytes the release of calcium (Ca2+) from the endoplasmic reticulum via the inositol 1, 4, 5-trisphosphate (IP3) pathway. This results in gliotransmission which elevates the presynaptic transmission probability rate (PR) causing weight potentiation and a gradual increase in postsynaptic neuronal firing, that eventually stabilizes. However, by capturing the complex interactions between IP3, generated from both GABA and the 2-arachidonyl glycerol (2-AG) pathway, and PR, this paper shows that this interaction not only gives rise to an initial weight potentiation phase but also this phase is followed by postsynaptic bursting behavior. Moreover, the model will show that there is a presynaptic frequency range over which burst firing can occur. The proposed model offers a novel cellular level mechanism that may underpin both seizure-like activity and neuronal synchrony across different brain regions

Aquaporin-4-dependent K(+) and water transport modeled in brain extracellular space following neuroexcitation.

Potassium (K(+)) ions released into brain extracellular space (ECS) during neuroexcitation are efficiently taken up by astrocytes. Deletion of astrocyte water channel aquaporin-4 (AQP4) in mice alters neuroexcitation by reducing ECS [K(+)] accumulation and slowing K(+) reuptake. These effects could involve AQP4-dependent: (a) K(+) permeability, (b) resting ECS volume, (c) ECS contraction during K(+) reuptake, and (d) diffusion-limited water/K(+) transport coupling. To investigate the role of these mechanisms, we compared experimental data to predictions of a model of K(+) and water uptake into astrocytes after neuronal release of K(+) into the ECS. The model computed the kinetics of ECS [K(+)] and volume, with input parameters including initial ECS volume, astrocyte K(+) conductance and water permeability, and diffusion in astrocyte cytoplasm. Numerical methods were developed to compute transport and diffusion for a nonstationary astrocyte-ECS interface. The modeling showed that mechanisms b-d, together, can predict experimentally observed impairment in K(+) reuptake from the ECS in AQP4 deficiency, as well as altered K(+) accumulation in the ECS after neuroexcitation, provided that astrocyte water permeability is sufficiently reduced in AQP4 deficiency and that solute diffusion in astrocyte cytoplasm is sufficiently low. The modeling thus provides a potential explanation for AQP4-dependent K(+)/water coupling in the ECS without requiring AQP4-dependent astrocyte K(+) permeability. Our model links the physical and ion/water transport properties of brain cells with the dynamics of neuroexcitation, and supports the conclusion that reduced AQP4-dependent water transport is responsible for defective neuroexcitation in AQP4 deficiency

A Computational Study of Astrocytic GABA Release at the Glutamatergic Synapse: EAAT-2 and GAT-3 Coupled Dynamics

Neurotransmitter dynamics within neuronal synapses can be controlled by astrocytes and reflect key contributors to neuronal activity. In particular, Glutamate (Glu) released by activated neurons is predominantly removed from the synaptic space by perisynaptic astrocytic transporters EAAT-2 (GLT-1). In previous work, we showed that the time course of Glu transport is affected by ionic concentration gradients either side of the astrocytic membrane and has the propensity for influencing postsynaptic neuronal excitability. Experimental findings co-localize GABA transporters GAT-3 with EAAT-2 on the perisynaptic astrocytic membrane. While these transporters are unlikely to facilitate the uptake of synaptic GABA, this paper presents simulation results which demonstrate the coupling of EAAT-2 and GAT-3, giving rise to the ionic-dependent reversed transport of GAT-3. The resulting efflux of GABA from the astrocyte to the synaptic space reflects an important astrocytic mechanism for modulation of hyperexcitability. Key results also illustrate an astrocytic-mediated modulation of synaptic neuronal excitation by released GABA at the glutamatergic synapse

Development and Analysis of Engineered Brain Cell Microenvironments Mimicking Healthy and Diseased Neuronal Circuits

Astrocytes and microglia (glial cells) are active elements of the brain maintaining numerous homeostatic functions. Disturbances result in worsening of neuro-inflammation, traumatic brain injury, and various stages of brain tumors. Glial cells contribute to homeostasis for dynamic second messengers in the CNS, including intracellular calcium concentration ([Ca2+] i). Calcium is a central secondary messenger which signals for example, through the N-methyl-D-aspartate (NMDA) glutamate receptor on the neuronal membrane. A large, dynamic Ca2+ influx ensues after glutamate binds to the NMDA receptor. This influx initiates several molecular mechanisms within the cell. Disturbances in calcium homeostasis can lead to neurological diseases such as epilepsy and major depressive disorder. In this project, we set out to gain a better understanding of the effect of glial density on neural signalling. This was done by accomplishing four main objectives: 1. Develop neural micro-environments with quantifiable variations in glial cell densities. 2. Use calcium imaging methods to analyze the calcium information processing capacity of the various neural micro-environment developed. 3. Develop mathematical tools for testing calcium dynamics iv 4. Study short term and interactions of novel biomaterial (CuHARS) used for tissue engineering in brain cell micro-environments (Ca+2 signaling as an indicator of cell “health”) To do so, tissue engineered microenvironments were constructed to test the effects of the glial cell density have on calcium information processing. We investigated the response of glia rich, mildly glia depleted, partially depleted, and severely depleted neuronal cultures to sub-maximal (nM to µM) glutamate concentrations using calcium imaging. This was used to assist in predicting and interpreting chaotic neural networks experimentally. Anti-mitotic agents, cytosine arabinoside (AraC), or 2-deoxy-5- fluorouridine (FdU) were used to inhibit proliferating glia and develop the three classes of glia density. Imaging was done with Fluo 3/AM, nine to fourteen days after plating. Neuronal cultures severely depleted (greater than sixty percent depletion) of glia responded to increasing glutamate additions with large, slightly unsynchronized responses with the greatest area under the curve (AUC) observed which returned to baseline the slowest of the three micro-environments developed. Cultures partially depleted (thirty to sixty percent depletion) of glia, responded to increasing glutamate addition with mid-sized, synchronized responses with lower AUC than cultures with severely depleted glial cells. Mildly depleted cultures behaved similarly to glia rich cultures. The difference between their AUC was not statistically significant. Studying how the brain behaves in altered systems, such as in glia depleted micro-environments will help us explore cell loss in the brain and develop more targeted protective strategies