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Neurobiology, Functions, and Relevance of Excitatory Amino Acid Transporters (EAATs) to Treatment of Refractory Epilepsy

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Abstract

Epilepsy is one of the most prevalent and devastating neurological disorders characterized by episodes of unusual sensations, loss of awareness, and reoccurring seizures. The frequency and intensity of epileptic fits can vary to a great degree, with almost a third of all cases resistant to available therapies. At present, there is a major unmet need for effective and specific therapeutic intervention. Impairments of the exquisite balance between excitatory and inhibitory synaptic processes in the brain are considered key in the onset and pathophysiology of the disease. As the primary excitatory neurotransmitter in the central nervous system, glutamate has been implicated in the process, with the glutamatergic system holding center stage in the pathobiology as well as in developing disease-modifying therapies. Emerging data pinpoint impairments of glutamate clearance as one of the key causative factors in drug-resistant disease forms. Reinstatement of glutamate homeostasis using pharmacological and genetic modulation of glutamate clearance is therefore considered to be of major translational relevance. In this article, we review the neurobiological and clinical evidence suggesting complex aberrations in the activity and functions of excitatory amino acid transporters (EAATs) in epilepsy, with knock-on effects on glutamate homeostasis as a leading cause for the development of refractory forms. We consider the emerging data on pharmacological and genetic manipulations of EAATs, with reference to seizures and glutamate dyshomeostasis, and review their fundamental and translational relevance. We discuss the most recent advances in the EAATs research in human and animal models, along with numerous questions that remain open for debate and critical appraisal. Contrary to the widely held view on EAATs as a promising therapeutic target for management of refractory epilepsy as well as other neurological and psychiatric conditions related to glutamatergic hyperactivity and glutamate-induced cytotoxicity, we stress that the true relevance of EAAT2 as a target for medical intervention remains to be fully appreciated and verified. Despite decades of research, the emerging properties and functional characteristics of glutamate transporters and their relationship with neurophysiological and behavioral correlates of epilepsy challenge the current perception of this disease and fit unambiguously in neither EAATs functional deficit nor in reversal models. We stress the pressing need for new approaches and models for research and restoration of the physiological activity of glutamate transporters and synaptic transmission to achieve much needed therapeutic effects. The complex mechanism of EAATs regulation by multiple factors, including changes in the electrochemical environment and ionic gradients related to epileptic hyperactivity, impose major therapeutic challenges. As a final note, we consider the evolving views and present a cautious perspective on the key areas of future progress in the field towards better management and treatment of refractory disease forms.

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Authors and Affiliations

  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia

    Aleksey V. Zaitsev & Ilya V. Smolensky

  2. Department of Experimental Neurobiology, National Institute of Mental Health, Topolová 748, 250 67, Klecany, Czech Republic

    Pascal Jorratt & Saak V. Ovsepian

  3. Department of Psychiatry and Medical Psychology, Third Faculty of Medicine, Charles University, Ruská 87, 100 00, Prague 10, Czech Republic

    Pascal Jorratt & Saak V. Ovsepian

  4. International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland

    Saak V. Ovsepian

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This research was funded by the Russian Foundation for Basic Research (RFBR), grant number 17–00-00408. SVO and PJ were supported by the project Sustainability for the National Institute of Mental Health, under grant number LO1611, with financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the NPU I program.

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AZ and IS performed the literature search and wrote the first draft. PJ and SO reviewed and revised the manuscript. The final manuscript was written by AZ and SO, and all authors contributed to and have approved the final version of this manuscript.

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Zaitsev, A.V., Smolensky, I.V., Jorratt, P. et al. Neurobiology, Functions, and Relevance of Excitatory Amino Acid Transporters (EAATs) to Treatment of Refractory Epilepsy. CNS Drugs 34, 1089–1103 (2020). https://doi.org/10.1007/s40263-020-00764-y

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