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.

mGlu3 metabotropic glutamate receptors as a target for the treatment of absence epilepsy. Preclinical and human genetics data / Celli, R.; Striano, P.; Citraro, R.; Di Menna, L.; Cannella, M.; Imbriglio, T.; Koko, M.; De Sarro, G.; Monn, J. A.; Battaglia, G.; van Luijtelaar, G.; Nicoletti, F.; Russo, E.; Leo, A.; Palotie, A.; Folkhalsan, A. -E. L.; Ruppert, A. -K.; Lal, D.; Thiele, H.; Altmuller, J.; Jabbari, K.; Nurnberg, P.; Sander, T.; Siren, A.; Becker, F.; Lerche, H.; Weber, Y.; Koeleman, B.; Caglayan, H.; Hjalgrim, H.; Moller, R.; Muhle, H.; Helbig, I.; Everett, K.; May, P.; Krause, R.; Balling, R.; Nabbout, R.; Zara, F.; Scala, M.; Iacomino, M.; Scudieri, P.; Bocciardi, R.; Balagura, G.; Minetti, C.; Riva, A.; Vari, M. S.; Amadori, E.; Perinelli, M.; Verrotti, A.; Baulac, S.; Kunz, W.. - In: CURRENT NEUROPHARMACOLOGY. - ISSN 1875-6190. - 21:1(2023), pp. 105-118. [10.2174/1570159X20666220509160511]

mGlu3 metabotropic glutamate receptors as a target for the treatment of absence epilepsy. Preclinical and human genetics data

Celli R.;Di Menna L.;Imbriglio T.;De Sarro G.;Battaglia G.;Nicoletti F.;Becker F.;May P.;Krause R.;Amadori E.;
2023

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.
2023
absence epilepsy; eeg; gaba; cortico-thalamo-cortical network; glutamate; human genetics; mglu3 receptors
01 Pubblicazione su rivista::01a Articolo in rivista
mGlu3 metabotropic glutamate receptors as a target for the treatment of absence epilepsy. Preclinical and human genetics data / Celli, R.; Striano, P.; Citraro, R.; Di Menna, L.; Cannella, M.; Imbriglio, T.; Koko, M.; De Sarro, G.; Monn, J. A.; Battaglia, G.; van Luijtelaar, G.; Nicoletti, F.; Russo, E.; Leo, A.; Palotie, A.; Folkhalsan, A. -E. L.; Ruppert, A. -K.; Lal, D.; Thiele, H.; Altmuller, J.; Jabbari, K.; Nurnberg, P.; Sander, T.; Siren, A.; Becker, F.; Lerche, H.; Weber, Y.; Koeleman, B.; Caglayan, H.; Hjalgrim, H.; Moller, R.; Muhle, H.; Helbig, I.; Everett, K.; May, P.; Krause, R.; Balling, R.; Nabbout, R.; Zara, F.; Scala, M.; Iacomino, M.; Scudieri, P.; Bocciardi, R.; Balagura, G.; Minetti, C.; Riva, A.; Vari, M. S.; Amadori, E.; Perinelli, M.; Verrotti, A.; Baulac, S.; Kunz, W.. - In: CURRENT NEUROPHARMACOLOGY. - ISSN 1875-6190. - 21:1(2023), pp. 105-118. [10.2174/1570159X20666220509160511]
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