Contusion brain damage in mice for modelling of post-traumatic epilepsy with contralateral hippocampus sclerosis: Comprehensive and longitudinal characterization of spontaneous seizures, neuropathology, and neuropsychiatric comorbidities

Traumatic brain injury (TBI) is a leading cause of acquired epilepsy referred to as post-traumatic epilepsy (PTE), characterized by spontaneous recurrent seizures (SRS) that start in the months or years following TBI. There is a critical need to develop small animal models for advancing the neurotherapeutics of PTE, which accounts for 20% of all acquired epilepsy cases. Despite many previous attempts, there are few PTE models with demonstrated consistency or longitudinal incidence of SRS, a critical feature for creating models for investigation of novel therapeutics for preventing PTE. Over the past few years, we have made in-depth updates and several advances to our mouse model of TBI in which SRS consistently occurs upon 24/7 monitoring for 4 months. Here, we show that an advanced cortical contusion damage in mice elicits a chronic state of PTE with SRS and robust epileptiform activity, along with cognitive comorbidities. We observed SRS in 33% and 87% of moderate and severe injury cohorts, respectively. Though incidence was higher in the severe cohort, moderate injury elicited a robust epileptogenesis. Progressive neuronal damage, neurodegeneration, and inflammation signals were evident in many brain regions; comorbid behavior and cognitive deficits were observed for up to 4-months. SRS onset was correlated with the inception of interneuron loss after TBI. Contralateral hippocampal sclerosis was unique and well correlated with SRS, confirming a potential network basis for epileptogenesis. Collectively, this mouse model exhibits a number of hallmark TBI sequelae reminiscent of human PTE. This model provides a vital tool for probing molecular pathological mechanisms and therapeutic interventions for post-traumatic epileptogenesis. Significance statement: TBI is a leading cause of post-traumatic epilepsy (PTE). Despite many attempts to create PTE in animals, success has been limited due to a lack of consistent spontaneous epileptic seizures after TBI. We present a comprehensive phenotype of PTE after contusion brain injury in mice, which exhibits robust spontaneous seizures along with neuronal loss, inflammation, and cognitive dysfunction. Our broad profiling of a TBI mouse reveals features of progressive, long-lasting epileptic activity, unique contralateral hippocampal sclerosis, and comorbid mood and memory deficits. The PTE mouse shows a striking consistency in recapitulating major pathological sequelae of human PTE. This mouse model will be helpful in assessing mechanisms and interventions for TBI-induced epilepsy and mood dysfunction.

Automated summary

This study comprehensively investigated post-traumatic epilepsy (PTE) in a mouse model, revealing that moderate contusion injury in mice leads to chronic PTE with spontaneous seizures and robust epileptiform activity, as well as cognitive comorbidities. Various experiments demonstrate the model's ability to replicate major pathological sequelae of human PTE.