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.
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Authors | 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, Antonio Leo |
Journal | Current neuropharmacology
(Curr Neuropharmacol)
Vol. 21
Issue 1
Pg. 105-118
( 2023)
ISSN: 1875-6190 [Electronic] United Arab Emirates |
PMID | 35579153
(Publication Type: Journal Article)
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Copyright | Copyright© Bentham Science Publishers; For any queries, please email at [email protected]. |
Chemical References |
- Receptors, Metabotropic Glutamate
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Topics |
- Rats
- Humans
- Animals
- Infant
- Epilepsy, Absence
(drug therapy, genetics, metabolism)
- Receptors, Metabotropic Glutamate
(genetics, metabolism)
- Electroencephalography
- Seizures
- Human Genetics
- Disease Models, Animal
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