4. Prevention of trauma-induced epileptogenesis in mice via manipulation of the network excitability

Publication date: November 2017
Source:Clinical Neurophysiology, Volume 128, Issue 11
Author(s): S. Soltani, J. Seigneur, S. Chauvette, I. Timofeev
A large proportion of patients with severe brain damage become epileptic several months to years after the trauma. The mechanisms leading to the development of epilepsy (epileptogenesis) are unknown. We hypothesize that brain damage leads to partial deafferentation and a drop in excitability of the affected area. To compensate, the brain employs a variety of mechanisms to restore this drop of excitability and if not properly controlled, this leads to epilepsy. We performed undercut in the somatosensory area in adult C57/BL6 mice and implanted LFP and EMG electrodes for continuous electrographic recordings for at least two months. We proposed to manipulate (increase or decrease) network activities in order to prevent/enhance epileptogenesis applying DREADD technology. Target cortical regions were injected with AAV-hM3D(Gq) or AAV-hM4D(Gi). Activation of the designed receptor in infected neurons was achieved by clozapine-N-oxide continuously injected via an osmotic pump. Activation of hM3D(Gq) leads to depolarization and increased firing in infected neurons, while the activation of hM4D(Gi) induces a hyperpolarization of neurons. If our hypothesis is true, we expect to obtain epileptogenesis in adult mice without DREADD manipulations, either abolition or strong reduction of epileptogenesis in hM3D(Gq) mice, and increased epileptogenesis symptoms in hM4D(Gi) mice. In the following weeks all adult mice without DREADD manipulations revealed recurrent seizure activities. Mice in which hM4D(Gi) was activated revealed earlier and more severe seizures. Mice with hM3D(Gq) activation did not reveal paroxysmal activities. These results will lead to the development of new preventive treatments of epileptogenesis induced by brain damage.Supported by CIHR and NSERC.



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