Astrocytes as Guardians of Neuronal Excitability: Mechanisms Underlying Epileptogenesis

Abstract

Astrocytes are key homeostatic regulators in the central nervous system and play important roles in physiology. After brain damage caused by e.g., status epilepticus, traumatic brain injury, or stroke, astrocytes may adopt a reactive phenotype. This process of reactive astrogliosis is important to restore brain homeostasis. However, persistent reactive astrogliosis can be detrimental for the brain and contributes to the development of epilepsy. In this review, we will focus on physiological functions of astrocytes in the normal brain as well as pathophysiological functions in the epileptogenic brain, with a focus on acquired epilepsy. We will discuss the role of astrocyte-related processes in epileptogenesis, including reactive astrogliosis, disturbances in energy supply and metabolism, gliotransmission, and extracellular ion concentrations, as well as blood-brain barrier dysfunction and dysregulation of blood flow. Since dysfunction of astrocytes can contribute to epilepsy, we will also discuss their role as potential targets for new therapeutic strategies.

Extracellular S100B alters spontaneous Ca2+fluxes in dopaminergic neurons via L-type voltage gated calcium channels: Implications for Parkinson’s disease

“…1D). These findings are significant because astrocytic coverage of neuropil is a critical determinant in modulating the excitability of neurons via mechanisms such as the secretion of astrocyte-derived factors, the clearance of neurotransmitters, and extracellular K + buffering (Verhoog, Holtman, Aronica, & van Vliet, 2020). The observed morphological differences in interaction of astrocytic processes with SNc DA neurons in combination with an increased S100B to TH expression ratio in the SNc when compared to the VTA, suggest that any abnormal increase in astrocytic secretion of S100B in the SNc could significantly alter the function of SNc DA neurons with relatively little effect on DA neurons within the VTA.…”

From Physiology to Pathology of Cortico-Thalamo-Cortical Oscillations: Astroglia as a Target for Further Research

“…Not only do they support synapses from a mechanical, metabolical as well as functional point of view, but they also participate in synaptic transmission and plasticity, neural network excitability and balance between excitation and inhibition (E/I) as active information integrators and processors ( 83 – 86 ). The contribution of the astroglial network to the pathophysiology of epilepsy encompasses a plethora of different molecular mechanisms which currently represent one of the most fruitful research topics in neuroscience ( 87 – 96 ). Pathological priming mechanisms of the astroglial network ultimately involve either E/I imbalance or enhanced network synchronization (or both simultaneously).…”

Back to Basics: A Role for Astrocyte Alkalization in Epileptogenesis

“…Disruptions in astrocyte function have been associated with hyperexcitability and epileptogenesis. 1 For example, high extracellular potassium (K þ ) levels can cause epileptiform activity in acute brain slices. Astrocytes clear K þ generated during synaptic activity from the extracellular space.…”

“…In addition to mediating extracellular ion and water balance, astrocytes are actively involved in processes including neuroinflammation, energy supply and metabolism, and maintenance of the blood-brain barrier. 1 Astrocytes also release many molecules, including glutamate, GABA, glycine, ATP, and BDNF, that can function as "gliotransmitters" to regulate neuronal excitability and synaptic transmission. It will be important to study multiple aspects of astrocyte activity in normal and hyperexcitable networks, as well as after seizures, to understand how dysregulation of astrocyte function contributes to the development of epilepsy.…”