Abstracts

Rationale: The development of spontaneous seizures remains a challenge in the treatment of epilepsy. While the molecular and cellular determinants of seizures and epilepsy have been described, only sporadic progress has been made when attempting to develop anti-epileptogenesis approaches. The metabotropic glutamate receptor mGlu7 inhibits neurotransmitter release from the glutamate and GABA terminals. We have previously shown that the tonic activity of the mGlu7 receptor prevents synchronous and potentially pathological oscillations (Front Neural Circuits. 2016 Apr 25;10:31.). Yet, the role of mGlu7 in seizure progression and its potential as a therapeutic target have not been explored, due to the paucity of pharmacological tools available. Here we investigated the effect of mGlu7 in a model of epileptogenesis. Methods: We performed a virtual high throughput screening based on homology sequence analysis of mGlu receptors followed by in silico docking of the identified molecules in the agonist binding site. We found and synthesized a series of mGlu7 receptor agonists with advantageous pharmacokinetics properties, such as brain penetration. We tested one of these molecules, LSP2-9166, in vivo in the epileptogenic environment provided by the repetitive injection of the convulsant pentylenetetrazole (PTZ kindling) in both wild-type and mGlu7 mutant mice. Video-electroencephalography (EEG) was used to follow seizure progression and immunohistochemistry (IHC) and qPCR were performed to analyze the impact of the treatments on markers of epileptogenesis. Other epileptogenesis models, such as the kainate model, were also being evaluated. Results: mGlu7 mutant mice showed a lower threshold for seizure sensitivity and progression, whereas wild-type mice treated with the mGlu7/4 agonist LSP2-9166 present a slower development of PTZ-induced seizures: at the end of the protocol, 60% of control animals developed seizures with convulsions while 90% of the treated animals were protected against convulsive seizures. This slowdown was associated with a EEG frequency profile showing a much weaker excitability and synchronization. Moreover, increased power spectrum of basal, interictal activity observed in control animals was countered by the mGlu7 agonist. suggesting that chronic activation of mGlu7 may help to protect the deleterious cognitive effects associated with epileptogenesis. The inflammatory and excitotoxicity processes which result in proliferation of microglia and activation of astrocytes were also reduced by treatment with the mGlu7 activator. Conclusions: Targeting mGlu7 has an impact on network remodelling, neuronal damage and associated neuro-vascular inflammation. mGlu7 activation have a protective effect which slows epileptogenesis and the establishment of an aberrant functioning of brain activity. Specific modulation of the mGlu7 receptor could represent a novel therapeutic approach to reduce pathological network remodelling. Funding: The study was supported by funding from the INSB (ITMM, Innovation Technologique pour les Maladies Mentales)