Reduction of Spontaneous Inhibitory Synaptic Activity in Experimental Heterotopic Gray Matter

Abstract

Chen, Huan-Xin and Steven N. Roper. Reduction of spontaneous inhibitory synaptic activity in experimental heterotopic gray matter. J Neurophysiol 89: 150 -158, 2003. 10.1152/jn.00325.2002. Neuronal heterotopia has a strong association with epilepsy, but the mechanisms that underlie this relationship are largely unknown. We have utilized the in utero irradiated rat model to study circuit abnormalities in experimentally induced subcortical heterotopic gray matter. Spontaneous and miniature inhibitory (IPSCs) and excitatory (EPSCs) postsynaptic currents were recorded from visualized heterotopic pyramidal neurons in in vitro hemispheric slices and compared with control neocortical pyramidal neurons using the whole cell patchclamp technique. The frequency of spontaneous and miniature IPSCs was significantly reduced in pyramidal neurons from heterotopic cortex. Amplitude and kinetics of IPSCs were not different between the two groups. Spontaneous and miniature EPSCs were not different between the two groups. Short-term synaptic plasticity of stimulusevoked EPSCs showed depression in heterotopic neurons and facilitation in control pyramidal neurons. This study shows a selective impairment of the GABAergic circuitry in experimental heterotopic gray matter. We have reported similar findings in normotopic dysplastic cortex from this model. Taken together, these studies demonstrate a pervasive defect in inhibition throughout the cortex of irradiated rats with cortical dysplasia and neuronal heterotopia. This may have important implications regarding cortical development and function following in utero injuries.

Dysfunction of Synaptic Inhibition in Epilepsy Associated with Focal Cortical Dysplasia

“…Despite these inherent limitations, it is interesting that some of the electrophysiological findings reported here have been described previously in rodent models of cortical malformation (Zhu and Roper, 2000;Calcagnotto et al, 2002;Chen and Roper, 2003). Human tissue samples, on the other hand, limit experimental design in that strict age-matched control samples from nonepileptic patients are rarely available for comparison.…”

“…Furthermore, this decreased inhibition, even in the absence of additional defects, could be sufficient for the generation of seizures, because even small reductions in GABA-mediated function were shown to induce abnormal electrical discharge (Powell et al, 2003;Cobos et al, 2005). Interestingly, a reduction in IPSC frequency was reported in a rodent model of cortical dysplasia (caused by prenatal irradiation) featuring hyperexcitability and rare spontaneous seizures (Zhu and Roper, 2000;Chen and Roper, 2003;Kellinghaus et al, 2004). In both human tissue and experimental models, this reduced IPSC frequency could result from a decreased release of GABA at presynaptic terminals or simply from an impairment of GABAergic terminals and/or cells within the FCD.…”

“…The little we do know about synaptic function in a malformed brain is derived primarily from animal model research. For example, rodent models of cortical dysplasia exhibit a reduction in IPSC frequency (Zhu and Roper, 2000;Calcagnotto et al, 2002;Chen and Roper, 2003) and reduced numbers of parvalbumin-positive interneurons (Rosen et al, 1998;Roper et al, 1999). Inhibitory dysfunction in a malformed brain might result from altered arrangement of GABAergic inputs, loss of interneurons, or abnormal neurotransmitter reuptake in regions of dysplasia.…”

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.…”

Reorganization of barrel circuits leads to thalamically-evoked cortical epileptiform activity

“…This paramicrogyral zone shows grossly normal cytoarchitectonic organization, however alterations in postsynaptic receptors and synaptic strength are present (DeFazio and Hablitz, 1999;DeFazio and Hablitz, 2000;Jacobs and Prince, 2005) as well as abnormal connectivity (Jacobs et al, 1999c;Rosen et al, 2000) and widespread reductions in the density of PV-containing GABAergic interneurons (Rosen et al, 1998; but see Schwarz et al 2000). Apparent loss of inhibitory neurons or decreases in functional inhibition has also been reported in cortical dysplasia produced by fetal irradiation (Chen and Roper, 2003;Roper et al, 1997;Roper, 1998;Zhu and Roper, 2000) and in human dysplastic cortex (Calcagmoto et al, 2005), and is a common finding in other models of chronic epileptogenesis (Ribak et al, 1986;Lowenstein et al, 1992;Buckmaster and Dudek, 1997;Cossart et al, 2001; reviewed in Prince and Jacobs, 1998)..…”