Gabapentin decreases epileptiform discharges in a chronic model of neocortical trauma

Li, Huifang; Graber, Kevin; Jin, Sha; McDonald, Whitney S.; Barres, Ben A.; Prince, David A.

doi:10.1016/j.nbd.2012.06.019

Cited by 49 publications

(76 citation statements)

References 87 publications

(147 reference statements)

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“…Astrocyte-secreted thrombospondins regulate excitatory synapse formation in the developing CNS, (Christopherson et al, 2005; Eroglu et al, 2009) and they have been shown to be upregulated following injury correlated with an increase in reactive astrocytosis (Lin et al, 2003; Li et al, 2012). To establish if thrombospondin levels are altered in our model, freeze lesion and sham lesion brains were probed for thrombospondin 1 and 2 (TSP1/2) immunoreactivity.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, whether upregulation of TSP and α2δ-1 reported here also occur in adult injuries remains to be seen. Data from other in vitro models (Li et al, 2012; Liauw et al, 2008) suggest that GBP could remain efficacious, but whether GBP would be widely useful following adult brain injury has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Rather, its therapeutic actions appear to be mediated by antagonizing the interaction of TSP and α2δ-1 (Eroglu et al, 2009; Eroglu, 2009). Recent studies have shown that GBP treatment prevented injury-induced increases in reactive astrocytosis and excitatory synaptogenesis (Li et al, 2012; Lo et al, 2011). Furthermore, GBP treatment attenuated cortical hyperexcitability in a model of posttraumatic epilepsy associated with upregulation of α2δ-1 (Li et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have shown that GBP treatment prevented injury-induced increases in reactive astrocytosis and excitatory synaptogenesis (Li et al, 2012; Lo et al, 2011). Furthermore, GBP treatment attenuated cortical hyperexcitability in a model of posttraumatic epilepsy associated with upregulation of α2δ-1 (Li et al, 2012). Given these findings, along with reports of increased reactive astrocytes in the FL model (Bordey et al, 2001; Campbell & Hablitz, 2008; Dulla et al, 2012), we hypothesized that treating FL animals with GBP during the latent period may attenuate later hyperexcitability in the FL model.…”

Section: Introductionmentioning

confidence: 99%

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

Lau

Hampton

Taylor-Weiner

et al. 2014

Neurobiology of Disease

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Lau

Hampton

Taylor-Weiner

et al. 2014

Neurobiology of Disease

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“…Increase in intrinsic excitability (47), selective excitatory synaptogenesis (48), and reduction in inhibitory transmission (14) were all reported to occur during epileptogenesis. Our recordings from neocortical pyramidal neurons indicate activity-dependent increase in excitability that does not require a prominent change in intrinsic properties and/or spontaneous synaptic transmission, and is probably astrocyte mediated (10).…”

Section: Discussionmentioning

confidence: 99%

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Levy

Milikovsky

Baranauskas

et al. 2015

The Journal of Immunology

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TGF-β1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-β1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-β signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, culminating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V pyramidal cells in neocortical slices obtained from IL-6–treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-β1–induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-β signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte–neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-β1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death.

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Axon growth and synaptic function: A balancing act for axonal regeneration and neuronal circuit formation in CNS trauma and disease

Kiyoshi

Tedeschi

2020

Developmental Neurobiology

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Axon regeneration failure following central nervous system (CNS) trauma and disease often leads to permanent functional disability. Promoting axon sprouting and regeneration of spared and injured axons as well as refinement of existing or de novo formation of neuronal circuits can attain neurological recovery (Hutson & Di Giovanni, 2019; Maier & Schwab, 2006). The development of neuronal circuits in the mammalian CNS is a dynamic process that requires coordinated epigenetic regulation of gene expression (Henikoff, 2008; Jaenisch & Bird, 2003). Genome-wide remodeling of the epigenetic landscape allows axon elongation, membrane expansion and navigation toward target areas as well as axon branching, synapse formation, and refinement to be spatially and temporally ordered (Kolodkin & Tessier

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Gabapentin decreases epileptiform discharges in a chronic model of neocortical trauma

Cited by 49 publications

References 87 publications

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

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

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

Axon growth and synaptic function: A balancing act for axonal regeneration and neuronal circuit formation in CNS trauma and disease

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