Table 2.
Roles of Group I mGluRs in epileptogenesis
| Receptor | Mechanism | Signaling pathway | Model organism | Epilepsy inducer | Reference |
|---|---|---|---|---|---|
| mGluR5 | Initiation of fast ripples | phospholipase Cβ1 ↑ →intracellular Ca2+ ↑ | Male Wistar rats | KA (0.8 μg/0.5 μL) | Medina-Ceja and Garcia-Barba, 2017 |
| mGluR5 | Increased astrocytic glutamate uptake | Changes in synaptic contact: IP3 signaling↑→number of Schaffer collateral synapses↑→enhanced glutamate uptake/GLT-1 expression/PKC-dependent phosphorylation | Adult male and female mice | KA (2 mg/mL) | Umpierre et al., 2019 |
| mGluR5 | Synthesis of amyloid-beta protein precursor | mGluR5/FMRP signaling (influenced by Aβ/PrPC/mGluR5 interactions) | 3×Tg-AD mice | Auditory stimuli (5 min, high-pitched siren, 120 dB) | Kazim et al., 2017; Westmark, 2019 |
| mGluR1/5 | Initiating SWDs | mGluR↓→GAT-1 protein↓/GABA uptake↓→SWDs↑ | Male spontaneously epileptic WAG/Rij rats, age-matched Wistar rats, Sprague-Dawley rats | Celli et al., 2020 | |
| Male WAG/Rij rats, male non-epileptic control Wistar rats | Crans et al., 2020 | ||||
| mGluR5 | Decreasing tumor necrosis factor α expression in immune cells (microglia and macrophages) | Enhanced innate immune response→ proinflammatory cytokine secretion→seizure development | C57BL/6J inbred male mice | DA strain of TMEV | Hanak et al., 2019 |
| C57BL/6J inbred male mice, MyD88-deficient mice | 2 DA strain of TMEV | Kirkman et al., 2010 | |||
| mGluR1/5 | mGluR5-dependent calcium transients | Gq-PLC-IP3 signaling→ calcium transients/activity of PKC↑→epileptogenesis | Long Evans rats and genetic absence epilepsy rats from Strasbourg model | Neyer et al., 2016 | |
| mGluR1/5 | Eliciting epileptiform discharges | PLCβ1 signaling: Gαq/11 subunit→PLCβ pathway→IP3 | Ten-week-old F1 homozygous and wild-type littermates from crosses of C57BL/6J(N8)PLCβ1+/+ and 129S4/SvJae(N8)PLC+/− | Chuang et al., 2001 | |
| mGluR5 | NMDA receptor activation | Activated glutamatergic synapses/in vivo kindling→activated group I mGluRs→epileptogenesis | Male Wistar rats | Tramadol (150 mg/kg) | Valian et al., 2021 |
| NMDA receptor↑→epileptogenesis/maintenance of seizures | Male Wistar rats (7–8-wk-old) | Pilocarpine (10 mg/kg with 30 min intervals) | Kovalenko et al., 2022 | ||
| mGluR5 | Reducing CaMKII activity | Protein kinase C mediated CaMKII phosphorylation at Ser901→ CaMKII↓→ limbic epilepsy | Embryonic neurons; HEK293T cells | McNamara et al., 2006; Park et al., 2008 | |
| mGluR1/5 | Contributing to the paroxysmal burst of multiple unit activities in CA1 region | Exogenous activation of mGluR→extrasynaptic NMDAR/suprathreshold depolarization→ paroxysmal burst | P5–P7 Wistar rats | TBOA (DL-threo-β-benzyloxyaspartic acid, 100 μM) | Molinari et al., 2012 |
| mGluR1/5 | Elevation of spontaneous spike frequency in cortical neurons | Group I mGluRs↓→Anaphase-promoting complex/cyclosome↑/casein kinase I↑→ Mdm2 ↓→p53↑→proteasomal degradation of Akt | p53f/+-Emx1-Cre+ mouse neurons | Liu et al., 2020 | |
| mGluR5 | Co-localization with norbin in neurons of epileptic brain | Norbin↓→mGluR5 signaling↓/ CaMKII ↑ | Adult male Sprague-Dawley rats | Pilocarpine hydrochloride (30 mg/kg) | Xu et al., 2017 |
| mGluR1 | DNA methylation | Hypermethylation of mGluR1 gene→prolonged febrile seizure ↑ | Adult Sprague-Dawley rats | KA (1.83 mg/kg) | Alese and Mabandla, 2019 |
| mGluR1/5 | Altering efficacy of synaptic connections | ↑mGluR1α in TLE→intracellular calcium↑→ altered efficacy of synaptic connections | Male Sprague-Dawley rats/TLE patients | KA (12.5 mg/kg) | Blumcke et al., 2000 |
CaMKII: Calcium/calmodulin-dependent protein kinase II; FMRP: fragile X mental retardation protein; GLT-1: glutamate transporter-1; IP3: Inositol 1,4,5-trisphosphate; KA: kainic acid; mGluR: metabotropic glutamate receptor; NMDA: N-methyl-D-aspartatic acid; PKC: protein kinase C; PLC: phospholipase C; SWD: spike-and-wave discharges; TMEV: Theiler’s murine encephalomyelitis virus.