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Neurobiology of disease DOI:10.1016/j.nbd.2014.08.022

Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation.

Publication TypeJournal Article
Year of Publication2014
AuthorsAndresen, L, Hampton, D, Taylor, A, Morel, L, Yang, Y, Maguire, J, Dulla, CG
JournalNeurobiology of disease
Date Published2014/08/23
ISSN0969-9961
Abstract

Developmental cortical malformations are associated with a high incidence of drug-resistant epilepsy. The underlying epileptogenic mechanisms, however, are poorly understood. In rodents, cortical malformations can be modeled using neonatal freeze-lesion (FL), which has been shown to cause in vitro cortical hyperexcitability. Here, we investigated the therapeutic potential of gabapentin, a clinically used anticonvulsant and analgesic, in preventing FL-induced in vitro and in vivo hyperexcitability. Gabapentin has been shown to disrupt the interaction of thrombospondin (TSP) with α2δ-1, an auxiliary calcium channel subunit. TSP/α2δ-1 signaling has been shown to drive the formation of excitatory synapses during cortical development and following injury. Gabapentin has been reported to have neuroprotective and anti-epileptogenic effects in other models associated with increased TSP expression and reactive astrocytosis. We found that both TSP and α2δ-1 were transiently upregulated following neonatal FL. We therefore designed a one-week GBP treatment paradigm to block TSP/α2δ-1 signaling during the period of their upregulation. GBP treatment prevented epileptiform activity following FL, as assessed by both glutamate biosensor imaging and field potential recording. GBP also attenuated FL-induced increases in mEPSC frequency at both P7 and 28. Additionally, GBP treated animals had decreased in vivo kainic acid (KA)-induced seizure activity. Taken together these results suggest gabapentin treatment immediately after FL can prevent the formation of a hyperexcitable network and may have therapeutic potential to minimize epileptogenic processes associated with developmental cortical malformations.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0969-9961(14)00253-8
DOI10.1016/j.nbd.2014.08.022
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25158291?dopt=Abstract