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

NEUROBIOLOGY OF DISEASE

卷:71

Article

Andresen, Lauren^1,2  Hampton, David¹  Taylor-Weiner, Amaro³  Morel, Lydie¹  Yang, Yongjie¹  Maguire, Jamie¹  Dulla, Chris G.¹ 

[1] Tufts Univ, Sch Med, Dept Neurosci, Boston, MA 02111 USA

[2] Tufts Univ, Sackler Sch Grad Biomed Sci, Neurosci Program, Boston, MA 02111 USA

[3] Broad Inst, Cambridge, MA 02142 USA

关键词: Epilepsy;    Glutamate;    Freeze lesion;    Gabapentin;    Thrombospondin;    Cortex;    Developmental cortical malformation;   

DOI  :  10.1016/j.nbd.2014.08.022

来源: Elsevier

【 摘 要 】

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 alpha 2 delta-1, an auxiliary calcium channel subunit. TSP/alpha 2 delta-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 alpha 2 delta-1 were transiently upregulated following neonatal FL We therefore designed a one-week GBP treatment paradigm to block TSP/alpha 2 delta-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. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

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