mGlu3 Metabotropic Glutamate Receptors as a Target for the Treatment of Absence Epilepsy: Preclinical and Human Genetics Data.
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Celli Roberta, Striano Pasquale, Citraro Rita, Di Menna Luisa, Cannella Milena, Imbriglio Tiziana, Koko Mahmoud, De Sarro Giovambattista, Monn James A, Battaglia Giuseppe, Luijtelaar Gilles Van, Nicoletti Ferdinando, Russo Emilio, Leo Antonio, EuroEPINOMICS CoGIE Consortium, Palotie Aarno, Folkha Anna-Elina Lehesjoki, Ruppert Ann-Kathrin, Siren Auli, Koeleman Bobby, Lal Dennis, Becker Felicitas, Caglayan Hande, Hjalgrim Helle, Muhle Hiltrud, Thiele Holger, Helbig Ingo, Altmuller Janine, Jabbari Kamel, Everett Kate, May Patrick, Nürnberg Peter, Møller Rikke, Nabbout Rima, Zara Federico, Scala Marcello, Iacomino Michele, Scudieri Paolo, Bocciardi Renata, Balagura Ganna, Minetti Carlo, Riva Antonella, Vari Maria Stella, Amadori Elisabetta, Perinelli Martina, Verrotti Alberto, Krause Roland, Balling Rudi, Baulac Stephanie, Sander Thomas, Kunz Wolfram, Lerche Holger, Weber Yvonne
Аннотация
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.