Dysfunction of Synaptic Inhibition in Epilepsy Associated with Focal Cortical Dysplasia

Abstract

Focal cortical dysplasia (FCD) is a common and important cause of medically intractable epilepsy. In patients with temporal lobe epilepsy and in several animal models, compromised neuronal inhibition, mediated by GABA, contributes to seizure genesis. Although reduction in GABAergic interneuron density has been reported in FCD tissue samples, there is little available information on the resulting physiological changes in synaptic inhibition and the potential contribution of these changes to epileptogenesis in the dysplastic human brain. Using visualized whole-cell patch-clamp recordings from identified neurons in tissue slices obtained from patients with FCD, we demonstrate that GABA A -receptor-mediated inhibition is substantially altered in regions of dysplasia. These alterations include a significant reduction in IPSC frequency and a potentially compensatory decrease in transporter-mediated GABA reuptake function; the latter is marked by a significant increase in the decay-time constant for evoked and spontaneous IPSCs and a lack of effect of the GABA transportinhibitor 1-[2([(diphenylmethylene)imino]oxy)ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride on IPSC kinetics. Immunohistochemical staining revealed a scattering of GABAergic interneurons across dysplastic cortex and striking reductions in GABA transporter expression. Together, these results suggest that profound alterations in GABA-mediated synaptic inhibition play an essential role in the process of epileptogenesis in patients with FCD.

mTOR Signaling in Epilepsy: Insights from Malformations of Cortical Development

“…Loss of Tsc1 or Pten in hippocampal neurons in vitro lead to an increase in the ratio of excitation to inhibition at the network level, although through divergent mechanisms (Weston et al 2014). These findings provide experimental support to observations in human tuber and FCDIIB specimens, which show reduced numbers of GABAergic inhibitory interneurons (White et al 2001;Calcagnotto et al 2005;Lamparello et al 2007).…”

Abnormal Network Activity in a Targeted Genetic Model of Human Double Cortex

“…In keeping with this, patch-clamp recordings show that the majority of ectopic neurons generate spikes with immature properties (half-width and amplitude) and exhibit a reduced number of glutamatergic synaptic events and a dramatic loss of GABAergic synaptic drive compared with control L2/3 neurons during the second postnatal week. A reduction of sIPSC frequencies was previously shown in intrahippocampal heterotopia in rats treated with methylazoxymethanol acetate (MAM rats) (Calcagnotto et al, 2002(Calcagnotto et al, , 2005 or in white matter heterotopia in rats that have been exposed to in utero gamma irradiation (Zhu and Roper, 2000;Chen and Roper, 2003). However, at the second postnatal week, DCX heterotopias display a more severe phenotype: most neurons did not display any GABA synaptic event.…”

GABAergic Synaptic Inhibition Is Reduced before Seizure Onset in a Genetic Model of Cortical Malformation

“…Studies performed in humans and other animal models have implicated disruptions in the GABAergic system in seizure activity. These disruptions include altered inhibitory drive (Smith et al, 1999;Zhu and Roper, 2000;Calcagnotto et al, 2002), alterations in GABA interneuron populations (Ferrer et al, 1994;Mathern et al, 1995;Jacobs et al, 1996;Marco et al, 1996;Hablitz and DeFazio, 1998;Rosen et al, 1998;Spreafico et al, 1998;Roper et al, 1999;Schwarz et al, 2000), changes in GABA A receptor subunits (DeFazio and Hablitz, 1999;Loup et al, 2000;Redecker et al, 2000;Coulter, 2001;Crino et al, 2001;White et al, 2001;Palma et al, 2005), and changes in GABA reuptake transporters (Calcagnotto et al, 2002(Calcagnotto et al, , 2005). An important remaining question is what events precipitate the onset of seizures against this background of reduced inhibition.…”