Abstracts

Rationale: It has been estimated that between one and two million persons in the United States are subject to traumatic brain injury (TBI) each year. These estimates do not include the oft-devastating injuries to members of our armed forces. In the US, the Center for Disease Control and Prevention estimates that more than 80,000 develop long-term disability related to TBI each year, and that 3.2 million individuals are living with such disabilities. In addition to injury-related neuromotor deficits, life-long morbidities can include co-morbid outcomes such as increased seizure susceptibility, epilepsy, cognitive dysfunction, and emotional disturbances. The development of preventive and ameliorative strategies could enormously impact these areas of medical need. Immediate and early seizures have been described in many models of TBI in rats. Studies in rats have also demonstrated increased seizure susceptibility following fluid-percussion injury (FPI). Moreover, >50% of rats exposed to FPI will develop spontaneous recurrent seizures if followed for sufficient post-injury periods (D ambrosio et al., 2009, Brain, 127(Pt 2):304-314; Kharatashivilli et al., 2006, Neurosci. 140:685-697). The FPI model in rats is highly reproducible. Despite this body of literature in rats, evidence for similar findings in mice is scant. The use of genetic mice models would greatly enhance mechanistic studies of post-traumatic epileptogenesis using the FPI model.Methods: We assessed the immediate behavioral response after lateral FPI in male C57Bl/6 mice (23-28g, n=10). A 2mm hole was drilled, with dura intact, in the skull over the left parietal cortex (anteroposterior: +1.5mm; mediolateral: -1.2.mm). FPI (1.5-1.7 atm) was delivered via a syringe attached to a leur-lock ending of the FPI apparatus on one end and to the hole in the mouse skull on the other end. Sham animals received identical treatment except no pressure pulse was delivered. Animals were observed for 30 min after recovery from anesthesia, and subsequently twice a day (for 10 min) for seven days.Results: Immediately after recovery from anesthesia, 83% (5/6) of FPI mice developed stage 2 and 3 seizures, according to Racine`s scale. The average total duration of these seizures was 394.3 29.5 s SD. The avg frequency of these seizures for each mouse was 14.7 6 SD. None of the sham operated mice (0/4) exhibited any type of seizure activity. Among the animals experiencing seizures, one developed tonic-clonic seizures lasting 90s.Conclusions: The results show that mice subjected to FPI develop motor seizures shortly after recovering from anesthetic. Previous studies in mice have demonstrated that FPI increases hyperexcitability in the hippocampus (Witgen et al., 2005, Neurosci., 133:1-15; Tran et al., 2006, J Neurotrauma, 23(9):1330 1342; Bonislawaki et al., 2007, Neurobiol Dis, 25:163 169). These data beget the enticing possibility for the study of post-traumatic seizure mechanisms in transgenic mice using the FPI model.