Journal
CEREBRAL CORTEX
Volume 28, Issue 8, Pages 2725-2740Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhx152
Keywords
excitatory networks; laser-scanning photostimulation; neocortex; post-traumatic epilepsy; prophylaxis
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Funding
- Neurological Institute of Neurological Disorders and Stroke at the National Institutes of Health [NS12151, NS090076, NS077623]
- Edward F. and Irene Thiele Pimley Research Fund
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Neocortical injury initiates a cascade of events, some of which result in maladaptive epileptogenic reorganization of surviving neural circuits. Research focused on molecular and organizational changes that occur following trauma may reveal processes that underlie human post-traumatic epilepsy (PTE), a common and unfortunate consequence of traumatic brain injury. The latency between injury and development of PTE provides an opportunity for prophylactic intervention, once the key underlying mechanisms are understood. In rodent neocortex, injury to pyramidal neurons promotes axonal sprouting, resulting in increased excitatory circuitry that is one important factor promoting epileptogenesis. We used laserscanning photostimulation of caged glutamate and whole-cell recordings in in vitro slices from injured neocortex to assess formation of new excitatory synapses, a process known to rely on astrocyte-secreted thrombospondins (TSPs), and to map the distribution of maladaptive circuit reorganization. We show that this reorganization is centered principally in layer V and associated with development of epileptiform activity. Short-term blockade of the synaptogenic effects of astrocytesecreted TSPs with gabapentin (GBP) after injury suppresses the new excitatory connectivity and epileptogenesis for at least 2 weeks. Results reveal that aberrant circuit rewiring is progressive in vivo and provide further rationale for prophylactic anti-epileptogenic use of gabapentinoids following cortical trauma.
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