Distribution and Initiation of Seizure Activity in a Rat Brain with Subcortical Band Heterotopia

Abstract

Summary:Purpose: Misplaced (heterotopic) cortical neurons are a common feature of developmental epilepsies. To better understand seizure disorders associated with cortical heterotopia, the sites of aberrant discharge activity were investigated in vivo and in vitro in a seizure-prone mutant rat (tish) exhibiting subcortical band heterotopia. Methods: Depth electrode recordings and postmortem assessment of regional cfos mRNA levels were used to characterize the distribution of aberrant discharge activity during spontaneous seizures in vivo. Electrophysiologic recordings of spontaneous and evoked activity also were performed by using in vitro brain slices from the tish rat treated with proconvulsant drugs (penicillin and 4-aminopyridine). Results: Depth electrode recordings demonstrate that seizure activity begins almost simultaneously in the normotopic and heterotopic areas of the tish neocortex. Spontaneous seizures induce c-fos mRNA in normotopic and heterotopic neocortical areas, and limbic regions. The threshold concentrations of proconvulsant drugs for inducing epileptiform spiking were similar in the normotopic and heterotopic areas of tish brain slices. Manipulations that blocked communication between the norniotopic and heterotopic areas of the cortex inhibited spiking in the heterotopic, but not the normotopic, area of the cortex. Conclusions: These findings indicate that aberrant discharge activity occurs in normotopic and heterotopic areas of the neocortex, and in certain limbic regions during spontaneous seizures in the tish rat. Normotopic neurons are more prone to exhibit epileptiform activity than are heterotopic neurons in the tish cortex, and heterotopic neurons are recruited into spiking by activity initiated in normotopic neurons. The findings indicate that seizures in the tish brain primarily involve telencephalic structures, and suggest that normotopic neurons are responsible for initiating seizures in the dysplastic neocortex.

Ictal EEG Patterns in Band Heterotopia

“…Similarly, our data do not definitively localize seizure onsets to the outer cortex, the ectopic band, or another subcortical structure. However, the expected correlation between clinical seizure type and ictal EEG supports the observation in the rat model of BH that seizures begin diffusely in the outer cortex (15).…”

“…Human functional imaging data indicate normal or above-normal cerebral glucose uptake in the ectopic grey matter in BH (11,13). Depth-electrode recordings from a patient with BH revealed spontaneous and independent epileptiform discharges arising in the heterotopic band (14), but in a rat model of BH seizures originated within the outer cortical mantle and spread rapidly to the ectopic band (15). A seizure discharge originating in the ectopic band, or propagating between the cortex and the subcortical band, could theoretically produce a highly unusual ictal EEG pattern, one not seen in patients without BH.…”

Reduction of Spontaneous Inhibitory Synaptic Activity in Experimental Heterotopic Gray Matter

“…Heterotopic neurons in this model also show reciprocal connections with cortical and subcortical brain structures (Schottler et al 1998). Metabolic studies show that the heterotopic cortex is active during in vivo seizures but in vitro slice studies suggest that epileptiform activity may actually originate in the overlying, normotopic cortex and spread to the heterotopic cortex through synaptic transmission (Chen et al 2000).…”

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

“…Although certain evidence indicates that neurons in the normotopic area of the tish cortex provide a key proconvulsant influence on neocortical circuitry (Chen et al, 2000), a similar role for heterotopic neurons is conceivable. Consequently, we investigated inhibitory synaptic transmission and interneuronal structure and function in cortical heterotopia.…”

“…Overlying the heterotopia is an area of the neocortex termed "normotopic cortex" that is thinner than normal neocortex but maintains proper orientation and lamination of its primary neurons (Lee et al, 1997(Lee et al, , 1999Schottler et al, 1998Schottler et al, , 2001. Electrophysiological studies have demonstrated that spontaneous seizure activity occurs in both normotopic and heterotopic areas of the adult tish neocortex, but that the normotopic area is more prone to develop aberrant discharge activity (Chen et al, 2000). Key advantages of the tish rat for studying functional disturbances associated with a cortical malformation are (1) the heterotopia are genetically heritable (i.e., no experimental manipulation is required to induce the malformation) and (2) the animals are naturally prone to develop recurrent spontaneous seizures (Lee et al, 1997;Chen et al 2000).…”