Postsynaptic Currents Prior to Onset of Epileptiform Activity in Rat Microgyria

Zsombok, Andrea; Jacobs, Kimberle M.

doi:10.1152/jn.00106.2007

Cited by 16 publications

(23 citation statements)

References 95 publications

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“…Importantly, later studies went on to show that increased excitatory input onto layer V pyramidal cells is present before the onset of epileptiform activity. This supports the hypothesis that network level changes occur during the latent period, before the onset of hyperexcitability at P14 (Zsombok & Jacobs, 2007). Changes in glutamate receptor expression and localization have also been reported in the FL model (Hagemann et al, 2003; Defazio & Hablitz, 2000; Zilles et al, 1998).…”

Section: Introductionsupporting

confidence: 87%

“…These changes may both drive later hyperexcitability and be useful targets for therapeutic intervention. We and others have shown that increases in EPSCs occur in the neonatal FL cortex by P7-P11 (Zsombok & Jacobs, 2007). This is in line with the hypothesis that increased excitatory input occurs during the latent period and may drive later hyperexcitability.…”

Section: Discussionmentioning

confidence: 80%

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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: Introductionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 80%

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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“…To confirm that excitatory hyperinnervation could be a cause rather than a result of hyperexcitability, we have previously examined whether it occurred prior to or after the onset of network hyperexcitability at P12. We found that there was an abrupt and consistent increase in the frequency of mEPSCs in PMR pyramidal neurons on P10 (Zsombok and Jacobs, 2007). When neonatally freeze-lesioned animals are given a second hit via hyperthermia on P10, they develop spontaneous seizures as adults (Scantlebury et al, 2005).…”

Section: Introductionmentioning

confidence: 64%

Early susceptibility for epileptiform activity in malformed cortex

Bell

Jacobs

2014

Epilepsy Research

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Despite early disruption of developmental processes, hyperexcitability is often delayed after the induction of cortical malformations. In the freeze-lesion model of microgyria, interictal activity cannot be evoked in vitro until postnatal day (P)12, despite the increased excitatory afferent input to the epileptogenic region by P10. In order to determine the most critical time period for assessment of epileptogenic mechanisms, here we have used low-Mg2+ aCSF as a second hit after the neonatal freeze lesion to examine whether there is an increased susceptibility prior to the overt expression of epileptiform activity. This two-hit model produced increased interictal activity in freeze-lesioned relative to control cortex. We quantified this with measures of incidence by sweep, time to first epileptiform event, and magnitude of late activity. The increase was present even in the P7-9 survival group, befor increased excitatory afferents invade, as well as in the P10-11 and P12-15 groups. In our young adult group (P28-36), the amount of interictal activity did not differ, but only the lesioned cortices produced ictal activity. We conclude that epileptogenic processes begin early and continue beyond the expression of interictal activity, with different time courses for susceptibility for interictal and ictal activity.

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“…Our findings are in contrast to studies in rodent malformation models 13,14,16 and human epileptic patients with heterotopia or focal cortical dysplasia 12,27,28 in which alterations in postsynaptic NMDA-type glutamate receptor subunit expression or function were reported. However, in a rodent model of polymicrogyria 20,29 and both the kainate and pilocarpine models of TLE, 18,19,30 a similar increase in EPSC frequency was observed, suggesting that enhanced excitatory drive may be a common feature of the epileptic brain.…”

Section: Discussionmentioning

confidence: 85%