Densities of glutamatergic and GABAergic presynaptic terminals are altered in experimental cortical dysplasia

Abstract

SUMMARYPurpose: Cortical dysplasia (CD) is a major cause of epilepsy in children and adults, but underlying mechanisms of epileptogenesis in this disorder are poorly understood. We have utilized the irradiated rat model to study an injury-based form of diffuse CD in rats. Prior studies in this model have shown reduced numbers of c-aminobutyric acid (GABA)ergic interneurons and reduced inhibitory synaptic currents in pyramidal cells in CD. We analyzed the number of excitatory and inhibitory presynaptic terminals in the neocortex of irradiated rats to better characterize altered connectivity in experimental CD. Methods: Antibodies to vesicular glutamate transporter 1 (VGLUT1), vesicular glutamate transporter 2 (VGLUT2), vesicular GABA transporter (VGAT), and parvalbumin (PV) were used to quantify glutamatergic and GABAergic presynaptic terminals in control and dysplastic cortex. Results: We found that the density of VGLUT1 terminals was increased in CD in comparison to layers IV, V, and VI in control cortex. VGLUT2 terminals were increased in CD compared to layers IV and VI. VGAT terminals were reduced in CD compared to layers II/III, IV, and V in controls as were PV-immunoreactive somata and terminals. Discussion: These findings suggest an overall increase in excitatory synaptic connectivity and decrease in inhibitory synaptic connectivity in CD in irradiated rat. We propose that these changes contribute to hyperexcitability in these animals and may contribute to epileptogenicity in some forms of human CD.

Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

“…As far as the experimental models of epilepsy are concerned, the density of VGAT terminals is reduced in an animal model of cortical dysplasia (Zhou and Roper, 2010), in pre-seizure seizure-sensitive gerbil (Kang et al, 2003) and picrotoxin-induced kindling rat hippocampi (Jiang et al, 2004), although VGAT-IR is unaltered in KA-induced seizures (Sperk et al, 2003). Contrasting evidence exists for changes in VGAT in epileptogenesis induced by pilocarpine.…”

TRPC3 mediates hyperexcitability and epileptiform activity in immature cortex and experimental cortical dysplasia

“…In utero irradiated rats are used as a model of CD (Roper 1998) and most closely resemble type IB CD in humans (Blümcke et al 2011). Our previous histological studies have demonstrated the loss of both interneurons (Deukmedjian et al 2004;Roper et al 1999;Zhou andRoper 2010, 2011) and GABAergic presynaptic terminals (Zhou and Roper 2010) and an increase of the density of glutamatergic terminals in dysplastic cortex (Zhou and Roper 2010). Electrophysiological studies have further confirmed an imbalance between excitatory and inhibitory synaptic inputs to pyramidal neurons (Chen and Roper 2003;Zhu and Roper 2000) and to GABAergic interneurons in irradiated rats with CD (Xiang et al 2006;Zhou et al 2009a;.…”

Quetiapine attenuates cognitive impairment and decreases seizure susceptibility possibly through promoting myelin development in a rat model of malformations of cortical development

“…Our results suggest that an underlying cause of seizure susceptibility may be related to the malformation of white matter. Fetal irradiation can produce a wide range of structural defects, which include agenesis of the corpus callosum (Roper et al, 1995), reduced numbers of dendrites (Zhou and Roper, 2010), and defective neuronal connections (Naylor et al, 2008). Thus, attenuation of cortical myelin dysplasia might also contribute to the quetiapine's protective effect on seizure susceptibility.…”