mGlu3 Metabotropic Glutamate Receptors as a Target for the Treatment of Absence Epilepsy: Preclinical and Human Genetics Data
Celli, Roberta; Striano, Pasquale; Citraro, Rita; Di Menna, Luisa; Cannella, Milena; Imbriglio, Tiziana; Koko, Mahmoud; De Sarro, Giovambattista; Monn, James A.; Battaglia, Giuseppe; van Luijtelaar, Gilles; Nicoletti, Ferdinando; Russo, Emilio; Koeleman, Bobby; Euro Epinomics-Cogie Consortium
(2023) Current Neuropharmacology, volume 21, issue 1, pp. 105 - 118
(Article)
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
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absence seizures; (ii) selective activation of mGlu3 receptors with LY2794193 affects the number and duration of spike-wave 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; real-time 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.
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Keywords: Absence epilepsy, cortico-thalamo-cortical network, EEG, GABA, glutamate, human genetics, mGlu3 receptors, Pharmacology, Neurology, Clinical Neurology, Psychiatry and Mental health, Pharmacology (medical)
ISSN: 1570-159X
Publisher: Bentham Science Publishers B.V.
Note: Publisher Copyright: © 2023 Bentham Science Publishers.
(Peer reviewed)