Traumatic Brain Injury induces persistent behavioural deficits that are rescued by the antiepileptic drug Levetiracetam

Abstract

Traumatic Brain Injury (TBI) produces acute challenges including seizures and neuroinflammation, and these then exacerbate lifelong difficulties including epilepsy, dementias, and anxiety. Applying antiepileptic drugs (AED) to manage acute seizures after TBI has promise to slow these progressive deficits. Levetiracetam (LEV) is an AED that mitigates seizures and neuroinflammation in various contexts. Here, we explore the utility of the larval zebrafish TBI model by documenting long term behavioural deficits (if any) induced by larval neurotrauma and whether they can be mitigated by LEV. We induced a mild blast TBI in three days-post-fertilization larvae, administered LEV (3 x 10-2 mM) for two days, and assessed behaviour in adults (9 +/- 1 or 22 +/- 1 months later). In open field tests, adult zebrafish that experienced TBI as larvae exhibited increased anxiety-like behaviour compared to sham-treated larvae, but this resolved by later adulthood. LEV treatment immediately following larval TBI did not significantly alter these outcomes. Novel object approach tests revealed sustained deficits in exploratory behaviour: adults that experienced larval TBI spent significantly less time investigating a novel object compared to sham controls throughout adulthood; this suggests long-term alterations in fear-related cognitive processing or threat evaluation. LEV treatment increased time spent near the novel object in early adulthood, but not later adulthood, suggesting a time-dependent efficacy of early pharmacological intervention. In sum, the larval zebrafish TBI model is suitable for investigating the progression and treatment of behavioural deficits. LEV showed only limited efficacy, but adjusted AED regimens have potential to mitigate long-term behavioural outcomes of TBI.