Validation of a novel animal model of post-traumatic epilepsy

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PTE (posttraumatic epilepsy) has been identified by the VA as a priority area for research. Current medical therapy for this condition is inadequate. No anticonvulsant has yet been demonstrated to be specifically effective against PTE. The animal model used for screening anticonvulsants (AEDs) greatly influences which compounds are identified. One consequence is that standard animal models seem to consistently identify compounds with similar actions. Since there is no good PTE animal model, AEDs especially effective for PTE have not been identified. Evidence of the benefits of novel animal models is the identification of levetiracetam (Keppra), currently the most prescribe drug for epilepsy. The more standard animal models had failed to identify its antiepileptic activity. Current PTE animal models such as lateral fluid percussion and controlled cortical impact are not practical for screening AEDs because the timing of seizures cannot be controlled. We have developed a model of penetration injury induced epilepsy. It is a variation on the theme of Dave Prince’s partial cortical isolation PTE model. The current model solves two critical weakness of the cortical undercutting model by utilizing the simpler anatomy of the hippocampus. First, sectioning the Schaffer Collateral that connect the CA3 and CA1 region of the rat hippocampus can create a region that predominantly contains reactive presynaptic changes (i.e. aberrant synaptic reorganization) and a region that contain postsynaptic changes (deafferentation induced dendritic hyperexcitability). This segregation of reactive mechanisms cannot be achieved in the cortex. Consequently, it makes it possible to more easily dissect the underlying complex mechanisms of PTE. Secondly, sectioning of the Schaffer Collateral does NOT block the spread of seizure from the seizure focus, as is the case with the cortical undercutting model. Thus, behavioral seizures can be observed. A third advantage from a drug discovery perspective is that, similar to the kindling model, seizures can be reliably evoked by a weak triggering electrical stimulus. This is operationally important for drug screening. One cannot wait for a seizure to occur when screening drugs. A useful animal model has to produce seizures on demand. In preliminary studies we have gathered compelling evidence that this novel PTE animal model can reliably produce behavioral and electrographic limbic seizures on demand. At this moment a compelling and unusual opportunity exists for a successful rational drug development. A novel therapeutic target for PTE, dendritic SK2 channels, has been identified. A novel animal model of PTE possessing the latter dysfunction has been developed. And a class of SK2 enhancers that can reverse that dysfunction has been discovered. We seek to make the most from the confluence of these discoveries and the opportunity they offer.