Transition of spike to seizure networks in the rat somatosensory and motor cortex requires mitogen‐activated protein kinase signaling

Objective During epileptogenesis, epileptic spikes emerge before seizures, yet the network mechanisms linking spike activity to seizure generation remain unclear. Previously, we showed that mitogen‐activated protein kinase kinase (MAP2K) inhibition reduces spiking in tetanus toxin (TeNT)‐injected rats. Here, we advanced the TeNT rat model to transition from spike to seizure networks to better understand the mechanisms underlying this process and determined the effect of MAP2K inhibition on both spikes and seizures. Methods Male rats received a single injection of TeNT into the somatosensory cortex (SC) or motor cortex (MC). Long‐term video‐electroencephalographic recordings over bilateral SC and MC were obtained for up to 140 days and analyzed using automated algorithms to quantify spike frequency, propagation, synchrony, and electrographic seizures. A subset of animals was treated orally with the MAP2K inhibitor CI‐1040 (250 mg/kg/day) on Days 14–35 to assess its effects on spike and seizure network formation. Results Low‐dose TeNT (60–120 ng/μL) injection into the SC produced progressive bihemispheric spiking without seizure development. In contrast, high‐dose TeNT (250 ng/μL) injection into the SC, but not MC, induced spontaneous electrographic seizures in five of eight animals. Before the first detected seizure, spikes were observed in both the ipsilateral and contralateral hemispheres. However, only animals whose propagation pattern became more synchronous developed seizures. Spike frequency did not differ between SC‐ and MC‐injected animals. Early inhibition of MAP2K using CI‐1040 reduced spike frequency and spike synchrony and was associated with an absence of detected seizures. Significance These findings demonstrate that the transition from interictal spikes to seizures in the rat sensory–motor system involves bihemispheric spike networks that transition into seizure networks. We show that SC is more prone to seizure development than MC and suggest that MAPK signaling contributes to bihemispheric spike synchronization, which could be important for seizure development.