Penetrating Injuries of the brain are a frequent cause of epilepsy in man, making it important to understandthe underlying pathogenetic mechanisms. Loss of inhibition has been found in a number of models ofepilepsy and may be important in posttraumatic human seizure disorders.
The specific aims of the proposedexperiments focus on two types of abnormality, found in a group of inhibitory cells within the partial corticalisolation model of posttraumatic epilepsy. These fast-spiking (FS) interneurons have a major influence on thecontrol of runaway activity in the cortex which, if unchecked, can lead to epileptic seizures. Anatomicalchanges in the axons of FS cells suggest that they make fewer functional contacts that would release GABAon themselves via 'autaptic1 synapses, and on excitatory pyramidal cells. They also have reductions in avital enzyme, the sodium pump. In vitro slices from chronically injured epileptogenic cortex together withpatch clamp techniques and dual recordings will be used to assess the functional disorders in inhibition thatoccur as a result of these axonal abnormalities. The long term goal of such experiments is to uncover linksbetween injury and the appearance of epilepsy that can be modified by strategies for prevention ortreatment, 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 agentsor neurotransmitters to boost pump activity and ameliorate seizure activity. The discovery that importantcortical inhibitory neurons are 'disconnected' from their targets after injury, rather than being killed, mayopen the way for approaches that will promote 'rewiring' of these connections to restore the balancebetween excitatory and inhibitory processes in the damaged areas.
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