Gliotransmission: A Novel Target for the Development of Antiseizure Drugs

Abstract

For more than a century, epilepsy has remained an incapacitating neurological disorder with a high incidence worldwide. Mesial temporal lobe epilepsy (TLE) is a common type of epilepsy without an effective pharmacological treatment. An increase in excitability and hypersynchrony of electrical neuronal activity during development are typically associated with an excitatory/inhibitory imbalance in the neuronal network. Astrocytes release gliotransmitters, which can regulate neuronal excitability and synaptic transmission; therefore, the classical neurocentric vision of the cellular basis of epileptogenesis has begun to change. Growing evidence suggests that the key contribution of astrocyte-to-neuron signaling in the mechanisms underlies the initiation, propagation, and recurrence of seizure activity. The aim of this review was to summarize current evidence obtained from experimental models that suggest how alterations in astroglial modulation of synaptic transmission and neuronal activity contribute to the development of this brain disease. In this article, we will summarize the main pharmacological, Ca2+-imaging, and electrophysiological findings in the gliotransmitter-mediated modulation of neuronal activity and their possible regulation as a novel cellular target for the development of pharmacological strategies for treating refractory epilepsies.

Loss of glutamate transportereaat2aleads to aberrant neuronal excitability, recurrent epileptic seizures and hypoactivity

“…For all these reasons, we propose to use our novel epilepsy model comprehensively to further the understanding of underlying epileptogenic mechanisms. We argue that our astroglial eaat2a -/mutant zebrafish model will provide an unexplored platform for identifying new treatment approaches, especially taking into account gliotransmission as a promising novel target [71][72][73][74] .…”

Human neuronal signaling and communication assays to assess functional neurotoxicity

“…A use case was given by the characterization of suramin and by showing how the system can be used to provide exact quantitative data on agonist and antagonist potencies and specificities. In the future, the identification of side effects of antiepileptic and anti-inflammatory drugs addressing purinergic receptors could be of interest, due to their wide distribution in the nervous system (Burnstock and Verkhratsky 2012;Di Virgilio and Vuerich 2015;Riquelme et al 2020).…”

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

“…Astrocytes do not only contribute to neural excitability and functioning by responding to neurotransmitter release and modification of extracellular ionic composition, they are also actively involved in neurotransmitter uptake and release, thus having a direct control of E/I balance ( Figure 3 ) ( 86 , 156 – 158 ). One of the key features of absence epilepsy are altered GABA levels ( 72 , 159 ) and GABAergic tonic and phasic inhibition in the cortico-thalamo-cortical network ( 25 , 73 ).…”