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

Neurobiol Dis
Authors
Keywords
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.

Year of Publication
2014
Journal
Neurobiol Dis
Volume
71
Pages
305-16
Date Published
2014 Nov
ISSN
1095-953X
URL
DOI
10.1016/j.nbd.2014.08.022
PubMed ID
25158291
PubMed Central ID
PMC4179994
Links
Grant list
R01-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