Antiepileptogenic repair of excitatory and inhibitory synaptic connectivity after neocortical trauma.
The "final common path" to epileptogenesis induced by cortical trauma and disease processes ultimately depends on changes in relative weights of excitatory and inhibitory synaptic activities in neuronal networks. Results of two experiments summarized here provide proof in principle that prophylaxis of posttraumatic epileptogenesis can result when antiepileptogenic treatments are focused on basic underlying synaptic mechanisms. (1) Brief gabapentin treatment after injury limits new excitatory synapse formation by preventing binding of thrombospondins to α2δ-1 receptors, resulting in long-lasting effects that limit aberrant excitatory connectivity and decrease epileptogenesis. (2) Fast-spiking (FS) interneurons are structurally and functionally abnormal in the partial cortical isolation and other models of epileptogenesis. Brain-derived neurotrophic factor (BDNF) supports growth and maintenance of GABAergic neurons during brain development, leading to the hypothesis that it might favorably affect injured interneurons. Partial activation of BDNF TrkB receptors with a small molecule reverses structural abnormalities in FS interneuronal terminals, increases the frequency of mIPSCs, and increases probability of GABA release. These changes are associated with significantly reduced spontaneous and evoked epileptiform bursts in vitro and increased threshold for pentylenetetrazole-induced seizures in vivo. Each of these treatments offers a potential promising approach to prophylaxis of injury-induced cortical epileptogenesis.
Epilepsy Research Laboratories, Stanford University School of Medicine, Stanford, CA, United States. Electronic address: daprince@stanford.edu.
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Prince
Epilepsy Research Laboratories, Stanford University School of Medicine, Stanford, CA, United States.
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Epilepsy Research Laboratories, Stanford University School of Medicine, Stanford, CA, United States.
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Parada
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000473:pathology*; D004827:Epilepsy / Q000188:drug therapy* / Q000209:etiology*; D006801:Humans; D019579:Neocortex / Q000187:drug effects* / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects*
D000927:Anticonvulsants
BDNF; Epileptogenesis; Gabapentin; Interneuron; Laser scanning photostimulation; Neocortex; Partial isolation; Prophylaxis; Pyramidal cell; Small molecule; Thrombospondin; TrkB; α2δ-1