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Current Neuropharmacology

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ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

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Research Article

mGlu3 Metabotropic Glutamate Receptors as a Target for the Treatment of Absence Epilepsy: Preclinical and Human Genetics Data

Author(s): Roberta Celli, Pasquale Striano, Rita Citraro, Luisa Di Menna, Milena Cannella, Tiziana Imbriglio, Mahmoud Koko, Euro Epinomics-Cogie Consortium, Giovambattista De Sarro, James A. Monn, Giuseppe Battaglia, Gilles Van Luijtelaar, Ferdinando Nicoletti, Emilio Russo* and Antonio Leo

Volume 21, Issue 1, 2023

Published on: 19 August, 2022

Page: [105 - 118] Pages: 14

DOI: 10.2174/1570159X20666220509160511

Price: $65

Abstract

Background: Previous studies suggest that different metabotropic glutamate (mGlu) receptor subtypes are potential drug targets for treating absence epilepsy. However, no information is available on mGlu3 receptors.

Objective: To examine whether (i) changes of mGlu3 receptor expression/signaling are found in the somatosensory cortex and thalamus of WAG/Rij rats developing spontaneous absence seizures; (ii) selective activation of mGlu3 receptors with LY2794193 affects the number and duration of spikewave discharges (SWDs) in WAG/Rij rats; and (iii) a genetic variant of GRM3 (encoding the mGlu3 receptor) is associated with absence epilepsy.

Methods: Animals: immunoblot analysis of mGlu3 receptors, GAT-1, GLAST, and GLT-1; realtime PCR analysis of mGlu3 mRNA levels; assessment of mGlu3 receptor signaling; EEG analysis of SWDs; assessment of depressive-like behavior.

Humans: search for GRM3 and GRM5 missense variants in 196 patients with absence epilepsy or other Idiopathic Generalized Epilepsy (IGE)/ Genetic Generalized Epilepsy (GGE) and 125,748 controls.

Results: mGlu3 protein levels and mGlu3-mediated inhibition of cAMP formation were reduced in the thalamus and somatosensory cortex of pre-symptomatic (25-27 days old) and symptomatic (6-7 months old) WAG/Rij rats compared to age-matched controls. Treatment with LY2794193 (1 or 10 mg/kg, i.p.) reduced absence seizures and depressive-like behavior in WAG/Rij rats. LY2794193 also enhanced GAT1, GLAST, and GLT-1 protein levels in the thalamus and somatosensory cortex. GRM3 and GRM5 gene variants did not differ between epileptic patients and controls.

Conclusion: We suggest that mGlu3 receptors modulate the activity of the cortico-thalamo-cortical circuit underlying SWDs and that selective mGlu3 receptor agonists are promising candidate drugs for absence epilepsy treatment.

Keywords: absence epilepsy, mGlu3 receptors, cortico-thalamo-cortical network, EEG, GABA, glutamate, human genetics

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