Abstracts

Rationale: Post-traumatic epilepsy (PTE) accounts for 20% of symptomatic epilepsy cases and 5% of all epilepsy cases. The mechanisms underlying how traumatic brain injury (TBI) leads to PTE remain unknown, which has limited the development of interventions for preventing or curing epilepsy after injury. The cortex is typically the most affected brain area at the onset of a TBI, but the thalamus is also an important site of dysfunction after injury because of its reciprocal connections with the cortex. One of the prominent characteristics of the thalamus is its ability to produce reverberating bursting activity, which is important for sensory processing, attention, and the maintenance of sleep. Thalamic dysfunction is also associated with various epileptic disorders and with cognitive dysfunction after TBI. However, it remains unknown how cortical TBI affects thalamic function, and whether the thalamus is involved in the development or expression of PTE. Furthermore, there is currently no cure for PTE. Methods: Controlled cortical impact model of PTE; patch-clamp electrophysiology in acute brain slices; chronic electrocorticography (ECoG); multi-unit thalamic electrophysiology in freely behaving mice; immunofluorescent staining in free-floating brain sections Results: Here we use histology and electrophysiological approaches in vitro and in vivo to determine if TBI in the somatosensory cortex alters the intrinsic membrane properties or the synaptic properties of thalamic neurons, and to test whether the thalamus could be a potential therapeutic target for preventing or curing PTE. We investigated these questions using the controlled cortical impact model of PTE in mice. We first observed neuronal loss in the functionally connected reticular thalamus (p=0.04, TBI vs. control littermates with craniotomy) and a significant increase in C1q (p=0.02, TBI vs. control littermates with craniotomy) and GFAP expression (p=0.02, TBI vs. control littermates with craniotomy) in the thalamus, using immunofluorescent staining of free-floating brain sections taken three weeks after cortical TBI. Using whole-cell patch-clamp recordings in thalamic slices, we showed that at three to four weeks after injury, cortical TBI leads to a long-term reduction in inhibitory postsynaptic currents in the reticular thalamic nucleus (p=0.01, TBI vs. control littermates with craniotomy), which has been associated with various epileptic disorders. Using simultaneous ECoG/video and thalamic depth recordings during free behavior, we showed that PTE seizures are characterized by robust high-frequency bursts in the somatosensory thalamus that are time-locked with the epileptic spikes. Preliminary results also suggest that optogenetic activation of the reticular thalamus is sufficient to induce and/or interrupt PTE seizures. Conclusions: We propose that the long-term synaptic changes in the reticular thalamic nucleus after TBI could be responsible, at least in part, for the development of PTE seizures and cognitive dysfunction. This study may lead to new therapeutic strategies for enhancing functional recovery while preventing seizures and/or epileptogenesis after injury. Funding: DOD EP150038Achievement Rewards for College Scientists Fellowship