CA3 principal cell activation triggers hypersynchronous-onset seizures in a mouse model of mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy and it is characterized by seizures that are often refractory to medications. Seizures in MTLE have two main patterns of onset that have been termed hypersynchronous (HYP) and low-voltage fast (LVF) and are believed to mainly depend on the activity of excitatory principal cells and inhibitory interneurons, respectively. In this study, we investigated whether unilateral open-loop optogenetic activation of CaMKII-positive principal cells in the hippocampus CA3 region favors the generation of spontaneous HYP seizures in kainic acid-treated (KA) CaMKII-ChR2 mice. Optogenetic activation of CA3 principal cells (1 Hz, 180 s ON, 220 s OFF) was implemented for 15 days after KA-induced status epilepticus. We found that both LVF and HYP seizures occurred in nonstimulated CaMKII-ChR2 (n = 6) and stimulated CaMKII-Cre (n = 5) mice. In contrast, optogenetic activation of principal cells in CaMKII-ChR2 mice (n = 5) triggered only HYP seizures that were characterized by high fast ripple (250-500 Hz) rates during the pre-ictal and ictal periods. These results provide firm evidence that in MTLE spontaneous seizures with different onset patterns depend on distinct neuronal network mechanisms of generation. They also demonstrate that HYP seizures occurring in vivo along with their associated fast ripples depend on the activity of principal cells in the CA3 region.NEW & NOTEWORTHY Previous evidence suggested that different seizure onset patterns rely on the activity of distinct neuronal populations. In this study, we show for the first time that in vivo optogenetic stimulation of CaMKII principal cells in kainic acid-treated mice triggers hypersynchronous-onset seizures that are associated with fast ripples. Our findings indicate that in patients with predominant HYP-onset seizures, anticonvulsant treatments should be aimed at limiting the firing of principal neurons in the seizure onset zone.