Abstracts

Rationale: The potential mechanisms of epileptogenesis after diffuse brain injury were studied using a model of closed-head rotational acceleration in swine. We performed in vivo extracellular recordings in the hippocampus in order to investigate changes in hippocampal function post injury. We compared responses to stimulation in sham and injured animals to corroborate previous results obtained with this model using in vitro slice electrophysiology.Methods: Changes in the hippocampus induced by diffuse brain injury were examined in a swine model of closed-head rotational acceleration. Male Yucatan swine (age 5 months) underwent coronal rotational acceleration that induces little or no loss of consciousness and minimal subdural bleeds, yet induces axonal pathology. Based on previous experiments we induced peak rotational velocities between 200 and 300 radians per second. In vivo electrophysiology allowed for examination of the changes in hippocampal function in sham versus injured animals. The cell layers of the hippocampus were mapped in every animal in order to ensure appropriate placement of a 32-channel recording probe. Baseline oscillatory activity and responses to stimulation in the hippocampus were analyzed using high-density recording arrays during simultaneous afferent stimulation. We visualized changes in the synaptic inputs post injury utilizing current source density and correlated the results to our previous in vitro hippocampal slice recordings. Paired-pulse paradigms were utilized in order to examine changes in excitability and neurotransmitter release, while theta burst stimulation was induced to provoke epileptiform activity. Hippocampal responses to stimulation were examined 7 days post injury. Results: Excitability of hippocampus was analyzed for epileptiform activity, synaptic facilitation and fiber volley amplitudes. Stimulation was performed in the Schaffer collaterals and the entorhinal cortex while recording from all layers of the dorsal hippocampus. Traces recorded in response to single and double pulse stimulations had significantly altered waveforms in CA1 region of hippocampus. Paired pulse facilitation in CA1 was deficient at 7 days post injury potentially due to changes in neurotransmitter release probability. There were also significant changes in responses to single pulse stimulation after theta burst stimulation, as well as altered baseline activity compared to sham. These alterations suggest an increased post-synaptic excitability or a shift in the excitation-inhibition balance of the local circuitry. The contribution of multiple injuries and the timing between them as a further augmenting factor to epileptogenesis is in progress, as is treatment with minocycline as a potential inhibitor of microglial activation post injury. Conclusions: These data suggest that diffuse brain injury may induce hippocampal axonal and synaptic dysfunction, and changes in hippocampal cellular excitability. Over time post injury these changes may lead to circuit-level changes in the hippocampus that will elicit sub-clinical epileptiform activity and potentially lower seizure thresholds.