The role of extracellular glutamate homeostasis dysregulated by astrocyte in epileptic discharges: a model evidence
- PMID: 38699615
- PMCID: PMC11061099
- DOI: 10.1007/s11571-023-10001-z
The role of extracellular glutamate homeostasis dysregulated by astrocyte in epileptic discharges: a model evidence
Abstract
Glutamate (Glu) is a predominant excitatory neurotransmitter that acts on glutamate receptors to transfer signals in the central nervous system. Abnormally elevated extracellular glutamate levels is closely related to the generation and transition of epileptic seizures. However, there lacks of investigation regarding the role of extracellular glutamate homeostasis dysregulated by astrocyte in neuronal epileptic discharges. According to this, we propose a novel neuron-astrocyte computational model (NAG) by incorporating extracellular Glu concentration dynamics from three aspects of regulatory mechanisms: (1) the Glu uptake through astrocyte EAAT2; (2) the binding and release Glu via activating astrocyte mGluRs; and (3) the Glu free diffusion in the extracellular space. Then the proposed model NAG is analyzed theoretically and numerically to verify the effect of extracellular Glu homeostasis dysregulated by such three regulatory mechanisms on neuronal epileptic discharges. Our results demonstrate that the neuronal epileptic discharges can be aggravated by the downregulation expression of EAAT2, the aberrant activation of mGluRs, and the elevated Glu levels in extracellular micro-environment; as well as various discharge states (including bursting, mixed-mode spiking, and tonic firing) can be transited by their combination. Furthermore, we find that such factors can also alter the bifurcation threshold for the generation and transition of epileptic discharges. The results in this paper can be helpful for researchers to understand the astrocyte role in modulating extracellular Glu homeostasis, and provide theoretical basis for future related experimental studies.
Keywords: Astrocyte; Epileptic discharges; Glutamate; Neural computational model; Neuron.
© The Author(s), under exclusive licence to Springer Nature B.V. 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Conflict of interest statement
Conflicts of interestThe authors declare that they have no conflict of interest.
Similar articles
-
Inhibition of p38 MAPK Signaling Regulates the Expression of EAAT2 in the Brains of Epileptic Rats.Front Neurol. 2018 Oct 29;9:925. doi: 10.3389/fneur.2018.00925. eCollection 2018. Front Neurol. 2018. PMID: 30429824 Free PMC article.
-
L-glutamate released from activated microglia downregulates astrocytic L-glutamate transporter expression in neuroinflammation: the 'collusion' hypothesis for increased extracellular L-glutamate concentration in neuroinflammation.J Neuroinflammation. 2012 Dec 23;9:275. doi: 10.1186/1742-2094-9-275. J Neuroinflammation. 2012. PMID: 23259598 Free PMC article.
-
Selective blockade of astrocytic glutamate transporter GLT-1 with dihydrokainate prevents neuronal death during ouabain treatment of astrocyte/neuron cocultures.Glia. 2002 Dec;40(3):337-49. doi: 10.1002/glia.10133. Glia. 2002. PMID: 12420313
-
Application of Novel Therapeutic Agents for CNS Injury: NAAG Peptidase Inhibitors.In: Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. Chapter 38. In: Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015. Chapter 38. PMID: 26269888 Free Books & Documents. Review.
-
Role of glutamate excitotoxicity and glutamate transporter EAAT2 in epilepsy: Opportunities for novel therapeutics development.Biochem Pharmacol. 2021 Nov;193:114786. doi: 10.1016/j.bcp.2021.114786. Epub 2021 Sep 24. Biochem Pharmacol. 2021. PMID: 34571003 Free PMC article. Review.
References
-
- Allam SL, Ghaderi VS, Bouteiller JMC, Legendre A, Ambert N, Greget R, Bischoff S, Baudry M, Berger TW. A computational model to investigate astrocytic glutamate uptake influence on synaptic transmission and neuronal spiking. Front Comput Neurosci. 2012;6:70. doi: 10.3389/fncom.2012.00070. - DOI - PMC - PubMed
LinkOut - more resources
Full Text Sources