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Neurobiol Dis 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-Weiner, A, Morel, L, Yang, Y, Maguire, J, Dulla, CG
JournalNeurobiol Dis
Volume71
Pages305-16
Date Published2014 Nov
ISSN1095-953X
KeywordsAge Factors, Amines, Animals, Animals, Newborn, Anticonvulsants, Calcium Channels, Cyclohexanecarboxylic Acids, Disease Models, Animal, Electric Stimulation, Epilepsy, Evoked Potentials, Excitatory Amino Acid Agonists, Excitatory Postsynaptic Potentials, Freezing, gamma-Aminobutyric Acid, Glial Fibrillary Acidic Protein, Glutamic Acid, In Vitro Techniques, Kainic Acid, Malformations of Cortical Development, Mice, Mice, Inbred C57BL, Neuroimaging, Patch-Clamp Techniques, Somatosensory Cortex, Thrombospondins
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

Alternate JournalNeurobiol. Dis.
PubMed ID25158291
PubMed Central IDPMC4179994
Grant ListR01-NS073574 / NS / NINDS NIH HHS / United States
R01 MH099554 / MH / NIMH NIH HHS / United States
R01-MH099554 / MH / NIMH NIH HHS / United States
R01 NS076885 / NS / NINDS NIH HHS / United States
P30 NS047243 / NS / NINDS NIH HHS / United States
R01-NS076885 / NS / NINDS NIH HHS / United States
R01 NS073574 / NS / NINDS NIH HHS / United States