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Neurobiol Dis. 2014 Nov;71:305-16. doi: 10.1016/j.nbd.2014.08.022. Epub 2014 Aug 23.

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

Author information

1
Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, SC201, Boston, MA, USA; Neuroscience Program, Sackler School of Graduate Biomedical Sciences, Tufts University, 136 Harrison Avenue, SC201, Boston, MA, USA.
2
Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, SC201, Boston, MA, USA.
3
Broad Institute, 301 Binney Street, 5066, Cambridge, MA 02142, USA.

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.

KEYWORDS:

Cortex; Developmental cortical malformation; Epilepsy; Freeze lesion; Gabapentin; Glutamate; Thrombospondin

PMID:
25158291
PMCID:
PMC4179994
DOI:
10.1016/j.nbd.2014.08.022
[Indexed for MEDLINE]
Free PMC Article

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