Gabapentin Prevents Progressive Increases in Excitatory Connectivity and Epileptogenesis Following Neocortical Trauma

Abstract

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 laser-scanning 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 astrocyte-secreted 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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