Emergence of focal cortical hyperexcitability in the murine tetanus toxin epilepsy model

Abstract Focal epilepsies are a heterogeneous group of neurological disorders that may be caused by a large variety of underlying brain lesions. Long-term quality of life prognosis is often poor, and treatment options are limited. Despite significant progress in animal model sophistication over the past decades, a deeper understanding of epileptogenic processes on a mesoscale and microscale circuit level is needed. Here we model focal epileptogenesis in mice using single intracortical tetanus toxin injections and employ chronic in vivo two-photon and widefield calcium imaging with simultaneous EEG and behavioral video recordings (“multimodal” recordings) to follow epileptogenic changes over time. We observe a moderate increase in global brain excitability on EEG but, more strikingly, a gradual emergence of brief but intense optically recorded epileptiform events (“microseizures”) that are spatially limited, peaking around 20-30 days after toxin injection and waning over the next 30 days. During these events, a majority of local neurons are recruited into extreme depolarization, yet there is considerable variability in duration and spatial coverage between events, depending on the proximity to the injection focus and the number of days elapsed since injection. Notably, EEG electrodes