Role of astrocyte purinergic signaling in epilepsy

Abstract

Epilepsy is characterized by unpredictable recurrent seizures resulting from hypersynchronous discharges from neuron assemblies. Increasing evidence indicates that aberrant astrocyte signalling to neurons plays an important role in driving the network hyperexcitability. Purinergic signalling is central in neuron-glia and glia-glia interactions and dysfunctions in communication pathways involving purinergic receptors have been reported in various CNS pathologies, such as Alzheimer disease, stroke, major depression, schizophrenia, and epilepsy. In the present review we will first discuss the mechanisms by which astrocytes influence neuronal activity. We will then review in more details recent evidence indicating that dysregulation of astrocyte purinergic signalling actively contributes to the appearance of abnormal neuronal activity in epilepsy.

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

“…In recent years, studies have shown an association between the glial water channel aquaporin-4 (AQP4) and Kir 4.1, forming an astrocytic protein complex responsible for removing potassium from the extracellular space, being an important mechanism in establishing a hyperpolarized neuronal membrane potential which may play an important role in epilepsy (Aronica et al, 2000;Das et al, 2012;Devinsky et al, 2013). Indeed, reduced expression of Kir 4.1 has been described in the hippocampus of patients with TLE (Das et al, 2012), where astrocytes showed deficits in potassium and glutamate uptake similar to those found in Kir 4.1 knockout animal models (Djukic et al, 2007;Chever et al, 2010;Nikolic et al, 2019). Furthermore, AQP4 knockout animals are also more susceptible to seizures and epilepsy (Dudek and Rogawski, 2005;Devinsky et al, 2013) and, in kainate-induced epileptic animal models, a reduction in AQP4 expression was also reported (Lee et al, 2012;Devinsky et al, 2013).…”

“…Besides glutamate homeostasis, astrocytes can also modulate water flow and potassium homeostasis in the extracellular space (Devinsky et al, 2013). Potassium concentration is regulated by astrocytes through its uptake by the sodium/potassium ATPase, sodium/potassium/chloride cotransporters, and input rectifier channels for potassium (Kir 4.1; Ransom et al, 2000;D'Ambrosio et al, 2002;Kofuji and Newman, 2004;Nikolic et al, 2019). Increased potassium concentration in the extracellular space can generate sustained neuronal depolarization and neuronal hyperexcitability (Walz, 2000;Devinsky et al, 2013;Nikolic et al, 2019), and evidence in the literature suggests an association between the uncontrolled increase of extracellular potassium levels and epilepsy, both in humans and in animal models (Steinhäuser et al, 2016).…”

Stretch-Induced Activation of Pannexin 1 Channels Can Be Prevented by PKA-Dependent Phosphorylation

“…Panx1 channels can be activated in physiological or pathological conditions, describing two states of permeability and conductance depending on the type of stimulation [8,9]. Panx1 participates in purinergic signaling through the release of ATP in different cell types, including neurons, astrocytes, erythrocytes, endothelial cells, gustatory cells, and immune system cells [6,[10][11][12]. The functional role of Panx1 channels is cell-type specific, e.g., in macrophages, neurons, and astrocytes.…”

Mice Lacking Connective Tissue Growth Factor in the Forebrain Exhibit Delayed Seizure Response, Reduced C-Fos Expression and Different Microglial Phenotype Following Acute PTZ Injection

“…Glial cells constitute the majority of cell population in the nervous system and play important roles in its structural development and functional maintenance. The statuses of astrocytes and microglia are closely related to neuronal activity [ 18 , 19 ] and have been associated with epileptogenesis [ 20 , 21 , 22 , 23 , 24 , 25 ]. Since Ctgf is expressed exclusively in the excitatory neurons in the mouse brain [ 17 ], our Fb Ctgf KO mouse model provides an excellent opportunity to explore the interactions between neurons and glia in the pathophysiology of epilepsy [ 25 ].…”