Penetrating Injuries of the brain are a frequent cause of epilepsy in man, making it important to understand the underlying pathogenetic mechanisms. Loss of inhibition has been found in a number of models of epilepsy and may be important in posttraumatic human seizure disorders.
The specific aims of the proposed experiments focus on two types of abnormality, found in a group of inhibitory cells within the partial cortical isolation model of posttraumatic epilepsy. These fast-spiking (FS) interneurons have a major influence on the control of runaway activity in the cortex which, if unchecked, can lead to epileptic seizures. Anatomical changes in the axons of FS cells suggest that they make fewer functional contacts that would release GABA on themselves via """"""""autaptic1 synapses, and on excitatory pyramidal cells. They also have reductions in a vital enzyme, the sodium pump. In vitro slices from chronically injured epileptogenic cortex together with patch clamp techniques and dual recordings will be used to assess the functional disorders in inhibition that occur as a result of these axonal abnormalities. The long term goal of such experiments is to uncover links between injury and the appearance of epilepsy that can be modified by strategies for prevention or treatment, such as development of targeted drugs. For example, if reductions in the """"""""sodium pump"""""""" contribute to cortical hyperexcitability and epileptogenesis, if may be possible to use pharmacological agents or neurotransmitters to boost pump activity and ameliorate seizure activity. The discovery that important cortical inhibitory neurons are """"""""disconnected"""""""" from their targets after injury, rather than being killed, may open the way for approaches that will promote """"""""rewiring"""""""" of these connections to restore the balance between excitatory and inhibitory processes in the damaged areas.
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