Astrocyte-neuron circuits in epilepsy

Abstract

The epilepsies are a diverse spectrum of disease states characterized by spontaneous seizures and associated comorbidities. Neuron-focused perspectives have yielded an array of widely used anti-seizure medications and are able to explain some, but not all, of the imbalance of excitation and inhibition which manifests itself as spontaneous seizures. Furthermore, the rate of pharmacoresistant epilepsy remains high despite the regular approval of novel anti-seizure medications. Gaining a more complete understanding of the processes that turn a healthy brain into an epileptic brain (epileptogenesis) as well as the processes which generate individual seizures (ictogenesis) may necessitate broadening our focus to other cell types. As will be detailed in this review, astrocytes augment neuronal activity at the level of individual neurons in the form of gliotransmission and the tripartite synapse. Under normal conditions, astrocytes are essential to the maintenance of blood-brain barrier integrity and remediation of inflammation and oxidative stress, but in epilepsy these functions are impaired. Epilepsy results in disruptions in the way astrocytes relate to each other by gap junctions which has important implications for ion and water homeostasis. In their activated state, astrocytes contribute to imbalances in neuronal excitability due to their decreased capacity to take up and metabolize glutamate and an increased capacity to metabolize adenosine. Furthermore, due to their increased adenosine metabolism, activated astrocytes may contribute to DNA hypermethylation and other epigenetic changes that underly epileptogenesis. Lastly, we will explore the potential explanatory power of these changes in astrocyte function in detail in the specific context of the comorbid occurrence of epilepsy and Alzheimer's disease and the disruption in sleep-wake regulation associated with both conditions.

Keywords: Adenosine; Astrocytes; Epilepsy; Glia; Metabolism; Therapy.

Fig. 1.. Schematic diagram depicting the mechanistic interplay in astrocytic function in epilepsy.

Mechanistically linked alterations in astrocytic function have been color coded. Red highlights seizures and the increased neuronal excitability that precipitates them. Purple highlights purine related changes. Orange highlights the sequalae of astrogliosis beyond its implications for adenosine signaling. Green highlights alterations in glutamatergic gliotransmission. Blue highlights the consequences of seizure-induced blood-brain barrier dysfunction.

Fig. 2.. The role of astrocytes in Alzheimer’s disease, epilepsy, and associated sleep-wake dysregulation.

Schematic diagram of the hypothesized mechanism by which astrocytes contribute to epilepsy, Alzheimer’s disease, and the associated disruption in sleep-wake regulation via disruption in adenosine signaling. Progressive or acute brain injury has been outlined with a red box to indicate that it is the causal point of origin. Red dotted arrows with question marks indicate known associations of unclear mechanistic cause.