Early susceptibility for epileptiform activity in malformed cortex

Abstract

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.

Laser-scanning astrocyte mapping reveals increased glutamate-responsive domain size and disrupted maturation of glutamate uptake following neonatal cortical freeze-lesion

“…This could be due to an increase in distal surface transporter density, to more directly couple with synapses in the hyperexcitable cortex. Previous studies have demonstrated an increase in mEPSPs in the paramicrogyral zone following FL (Jacobs and Prince, 2005 ; Bell and Jacobs, 2014 ), suggesting there may be an increased demand for glutamate uptake.…”

“…In the FL model, acute cortical brain slices generate epileptiform activity after P12–14 (Jacobs et al, 1996 , 1999 ; Bell and Jacobs, 2014 ). This phenotype is mainatined in the mouse FL model (Figure 1B ) (Andresen et al, 2014 ).…”

“…The freeze lesion (FL) model of cortical malformation is used to model these conditions and closely approximates human polymicrogyria (Dvorak et al, 1978 ; Jacobs et al, 1996 , 1999 ). Briefly, mouse pups are anesthetized on the day of birth (P0), and a 1 by 1.5 mm copper freezing probe cooled to −50 to −60°C is applied to the exposed skull for 5 s. Following neonatal FL, a microgyrus forms and the surrounding cortical circuitry (paramicrogyral zone) generates epileptiform activity beginning at P12–14 (Jacobs et al, 1996 , 1999 ; Andresen et al, 2014 ; Bell and Jacobs, 2014 ). In addition to changes in neuronal systems, astroglial cells are also altered in the FL model (Bordey and Sontheimer, 1998 ) and previous studies show that alterations in glutamate uptake occur (Campbell and Hablitz, 2008 ; Dulla et al, 2012 ).…”

Epilepsy and EEG Abnormalities in Congenital Zika Syndrome

“…9,24 There are animal models to estimate the risk of epilepsy in a malformed cortex. 25 Even in children who were not born with microcephaly, neuroimaging changes can be severe and cause a substantial risk of epilepsy. 18…”

Continuous epileptiform discharges during sleep as an evolutionary pattern in patients with congenital Zika virus syndrome

“…One of the reasons for drug‐resistant epilepsy is the nature of the CNS that occurs in this syndrome. The severe pattern of brain abnormalities is a determinant for the occurrence of cortical epileptogenicity with abnormal EEG findings 29 . Most patients with continuous ED were drug‐resistant (72.7%) and were under polytherapy (86.4%), whereas in the others, 45.2% were drug‐resistant and 51.6% were under polytherapy.…”