The mGlu7 receptor provides protective effects against epileptogenesis and epileptic seizures

Abstract

Finding new targets to control or reduce seizure activity is essential to improve the management of epileptic patients. We hypothesized that activation of the pre-synaptic and inhibitory metabotropic glutamate receptor type 7 (mGlu7) reduces spontaneous seizures.We tested LSP2-9166, a recently developed mGlu7/4 agonist with unprecedented potency on mGlu7 receptors, in two paradigms of epileptogenesis. In a model of chemically induced epileptogenesis (pentylenetetrazol systemic injection), LSP2-9166 induces an antiepileptogenic effect rarely observed in preclinical studies. In particular, we found a bidirectional modulation of seizure progression by mGlu4 and mGlu7 receptors, the latter preventing kindling. In the intra-hippocampal injection of kainic acid mouse model that mimics the human mesial temporal lobe epilepsy, we found LSP2-9166 reduced seizure frequency and hippocampal sclerosis. LSP2-9166 also acts as an anti-epileptic drug on established seizures in both models tested. Specific modulation of the mGlu7 receptor could represent a novel approach to reduce pathological network remodeling.

Chemogenetic Activation of Feed-Forward Inhibitory Parvalbumin-Expressing Interneurons in the Cortico-Thalamocortical Network During Absence Seizures

“…According to the literature, absence-SWDs can be induced in different mice and rat models using i.p. injections of PTZ at doses between 10 and 40 mg/kg (Marescaux et al, 1984;Snead et al, 2000;Girard et al, 2019;Van Erum et al, 2019). In this study, simultaneous video/EEG data showed that 10 mg/kg of PTZ did not induce seizures in any of the mice tested (Figure 2B), whereas doses of ≥30 mg/kg PTZ induced severe tonic-clonic seizures (Figure 2D).…”

“…However, some other studies have reported that increasing the concentration of PTZ from 40 to 70 mg/kg, substantially decreases the time of onset of first observed seizure from ∼5 min to ∼1 min (Medina et al, 2001;Schwaller et al, 2004). Likewise, Girard et al (2019) found that latency to seizure was decreased in mice injected with 60 mg/kg compared to animals injected with PTZ doses of 30-50 mg/kg. Van Erum et al (2020) recently reported genotype and age-related differences in susceptibility and onset of PTZ-induced seizures in mice.…”

Phenotypic profiling of mGlu7 knockout mice reveals new implications for neurodevelopmental disorders

“…mGlu 7 activation would be predicted to reduce seizures, as shown by a recent report that the mGlu 7 agonist LSP2-9166 exhibits efficacy in two distinct models of chemicallyinduced epilepsy. 49 We also report alterations in sleep architecture in female Grm7 −/− mice assessed by EEG across time from 8 to 20 weeks of age. The balance of glutamate and GABA function is known to regulate sleep, 50 and normal sleep is critical for memory consolidation.…”

Gelatinase Biosensor Reports Cellular Remodeling During Epileptogenesis

“…For EEG recording, six mice were implanted right after KA intrahippocampal injection, at the same coordinates with a bipolar tungsten electrode, as well as skull cortical electrodes on the frontoparietal bone and a reference electrode on the occipital bone. EEG activity was recorded as previously described (Girard et al, 2019) every 2 days during the first week, and then once a week. Briefly, micro connectors on freely moving animals were plugged into an EEG amplifier (Pinnacle Technology Inc.).…”

“…We next used ACPPs to report gelatinase activity in vivo, in a mice model of epileptogenesis. We and others have previously shown that a single intrahippocampal injection of kainic acid (KA) in the right hemisphere of the brain initiates cellular remodeling leading to focal TLE (Bouilleret et al, 1999;Girard et al, 2019). We injected mice unilaterally with KA and ACPPs in both ipsilateral and contralateral sides ( Figure 3A).…”