title: Gabapentin attenuates hyperexcitability in the freeze-lesion model of developmental cortical malformation.
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.
authors.affiliation: 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.
authors.forename: Lauren
authors.initials: L
authors.lastname: Andresen
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, SC201, Boston, MA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hampton
authors.affiliation: Broad Institute, 301 Binney Street, 5066, Cambridge, MA 02142, USA.
authors.forename: Amaro
authors.initials: A
authors.lastname: Taylor-Weiner
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, SC201, Boston, MA, USA.
authors.forename: Lydie
authors.initials: L
authors.lastname: Morel
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, SC201, Boston, MA, USA.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, SC201, Boston, MA, USA.
authors.forename: Jamie
authors.initials: J
authors.lastname: Maguire
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, SC201, Boston, MA, USA.
authors.forename: Chris G
authors.initials: CG
authors.lastname: Dulla
mesh_terms: D000367:Age Factors; D000588:Amines / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000627:therapeutic use*; D015220:Calcium Channels / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004827:Epilepsy / Q000188:drug therapy* / Q000209:etiology*; D005071:Evoked Potentials / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005615:Freezing / Q000009:adverse effects; D000077206:Gabapentin; D005904:Glial Fibrillary Acidic Protein; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity; D054220:Malformations of Cortical Development / Q000150:complications* / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D059906:Neuroimaging; D018408:Patch-Clamp Techniques; D013003:Somatosensory Cortex / Q000254:growth & development / Q000293:injuries*; D019699:Thrombospondins / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
chemical_list: D000588:Amines; D000927:Anticonvulsants; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D019699:Thrombospondins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D007608:Kainic Acid
keywords: Cortex; Developmental cortical malformation; Epilepsy; Freeze lesion; Gabapentin; Glutamate; Thrombospondin