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

Abstract

The ability of astrocytes to rapidly clear synaptic glutamate and purposefully release the excitatory transmitter is critical in the functioning of synapses and neuronal circuits. Dysfunctions of these homeostatic functions have been implicated in the pathology of brain disorders such as mesial temporal lobe epilepsy. However, the reasons for these dysfunctions are not clear from experimental data and computational models have been developed to provide further understanding of the implications of glutamate clearance from the extracellular space, as a result of EAAT2 downregulation: although they only partially account for the glutamate clearance process. In this work, we develop an explicit model of the astrocytic glutamate transporters, providing a more complete description of the glutamate chemical potential across the astrocytic membrane and its contribution to glutamate transporter driving force based on thermodynamic principles and experimental data. Analysis of our model demonstrates that increased astrocytic glutamate content due to glutamine synthetase downregulation also results in increased postsynaptic quantal size due to gliotransmission. Moreover, the proposed model demonstrates that increased astrocytic glutamate could prolong the time course of glutamate in the synaptic cleft and enhances astrocyte-induced slow inward currents, causing a disruption to the clarity of synaptic signalling and the occurrence of intervals of higher frequency postsynaptic firing. Overall, our work distilled the necessity of a low astrocytic glutamate concentration for reliable synaptic transmission of information and the possible implications of enhanced glutamate levels as in epilepsy.

Astrocytes—The Ultimate Effectors of Long-Range Neuromodulatory Networks?

“…Similar to how controlling [K + ] e can influence synaptic activity, astrocytes can also release the gliotransmitters glutamate and D-serine to affect synaptic function. Computational modeling suggests astrocytic glutamate release disrupts the occurrence of high-frequency post-synaptic firing (Flanagan et al, 2018) and both short-and long-term plasticity (De Pittà and FIGURE 2 | Perisynaptic K + buildup can decrease neurotransmitter release. (A) 50 Hz stimulation trains lead to the accumulation of extracellular K + that theoretically depolarizes membranes reducing presynaptic action potentials with a subsequent reduction in neurotransmitter release as evident by post-synaptic fEPSPs.…”

Astrocyte as Spatiotemporal Integrating Detector of Neuronal Activity

“…Intense modeling efforts have been devoted in recent years to understand the functional role of astrocytic modulation of the neuronal communication (see Oschmann et al, 2018 for a recent review, Kanakov et al, 2019). There are several biophysical studies of astrocytic influence on post- and presynaptic neuronal activity (De Pittà et al, 2011; Gordleeva et al, 2012; Tewari and Majumdar, 2012a,b; Tewari and Parpura, 2013; De Pittà and Brunel, 2016; Flanagan et al, 2018). However, these works did not account for the impact of spatiotemporal patterns of calcium dynamics in astrocyte, i.e., the spatial distribution of the calcium activity was neglected.…”

Neuroprotective Effects of Dammarane-Type Saponins from Panax notoginseng on Glutamate-Induced Cell Damage in PC12 Cells

“…The structures of compounds 1-9 (▶ Fig. 1) were identified by means of spectral analysis, and determined as notoginsenoside R 1 (1), notoginsenoside R 2 (2), ginsenoside Rh 1 (3), protopanaxatriol (4), ginsenoside Rg 1 (5), ginsenoside Rg 2 (6), ginsenoside U (7), pseudoginsenoside RT 3 (8), and 6-O-(β-D-glucopyranosyl)-20-O-(β-D-xylopyranosyl)-3β,6α,12β,20(S)-tetrahydroxydammar-24-ene (9). The detailed data and references are shown in the Supporting Information.…”