Dynamic interaction of local and transhemispheric networks is necessary for progressive intensification of hippocampal seizures

The detailed mechanisms of progressive intensification of seizures often occurring in epilepsy are not well understood. Animal models of kindling, with progressive intensification of stimulation-induced seizures, have been previously used to investigate alterations in neuronal networks, but has been obscured by limited recording capabilities during electrical stimulations. Remote networks in kindling have been studied by physical deletions of the connected structures or pathways, inevitably leading to structural reorganisations and related adverse effects. We used optogenetics to circumvent the above-mentioned problems inherent to electrical kindling, and chemogenetics to temporarily inhibit rather than ablate the remote interconnected networks. Progressively intensifying afterdischarges (ADs) were induced by repetitive photoactivation of principal neurons in the hippocampus of anaesthetized transgenic mice expressing ChR2. This allowed, during the stimulation, to reveal dynamic increases in local field potentials (LFPs), which coincided with the start of AD intensification. Furthermore, chemogenetic functional inhibition of contralateral hippocampal neurons via hM4D(Gi) receptors abrogated AD progression. These findings demonstrate that, during repeated activation, local circuits undergo acute plastic changes with appearance of additional network discharges (LFPs), leading to transhemispheric recruitment of contralateral dentate gyrus, which seems to be necessary for progressive intensification of ADs.