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Epilepsy Curr. 2006 May; 6(3): 96–98.
PMCID: PMC1464163

Disordered Migration of Interneurons within Focal Cortical Dysplasia

Jaideep Kapur, MD, PhD

Dysfunction of Synaptic Inhibition in Epilepsy Associated with Focal Cortical Dysplasia

Calcagnotto ME, Paredes MF, Tihan T, Barbaro NM, Baraban SC

J Neurosci 2005;25(42):9649–9657 [PubMed]

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 GABAA-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.


Cortical dysplasias, also referred to as cortical malformations, neuronal migration disorders, or cortical dysgenesis, are a common cause of medically refractory epilepsy, especially in children. Focal cortical dysplasia constitutes a distinct neuropathological entity, characterized by the presence of cortical dyslamination, ectopic neurons, and in some patients, the presence of cytomegalic neurons and balloon cells. When medical management of seizures fails, these patients are evaluated for surgical resection of the seizure focus with a combination of electrophysiological and imaging techniques (1). Although protocols used for presurgical evaluation of seizure focus and cortical dysplasias vary, minimally they include high-resolution MRI scans of the lesion, video-EEG monitoring with scalp electrodes and multiple contact grids, and depth electrodes. The electrophysiological and imaging techniques serve complementary functions. MRI discloses abnormal gyral patterns, shallow sulci, increased cortical thickness, poor gray–white distinction, and increased intensity of subcortical T2 signal. Ictal EEG discharges can be recorded from dysplastic cortex by scalp recordings and electrocorticography. Slices of dyplastic cortex do not demonstrate spontaneous seizures but possess a high propensity to generate epileptiform discharges in response to potassium channel blockers.

A key challenge in epilepsy research is to understand the neurobiological mechanisms underlying seizure generation in patients with cortical dysplasia. Two approaches for studying this problem have emerged: study of animal models of cortical dysplasias and analysis of tissue removed from patients. Animal models of cortical dysplasia offer many advantages: they allow investigation of early stages of the disease prior to onset of spontaneous seizures, remove the confounding effect of drug treatment, and provide suitable control tissue. Animal models of cortical dysplasia have limitations; for example, the in utero irradiation model does not produce giant and balloon cells, and in the methylazoxymethanol model, neocortex is minimally affected.

Studies on human tissue are exciting because they offer an opportunity to directly evaluate pathogenic mechanisms. A number of neuropathological and immunohistochemical studies of human cortical dysplasias have been performed and have generated a list of abnormalities found in dysplastic tissue (2) These include increased expression of NR2A/B subunit of N-methyl-d-aspartate (NMDA) receptor selectively in the dysplastic neurons, increased expression of GluR2/3 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors in dysplastic and giant cells, and reduced parvalbumin and calbindin D28K-immunoreactive interneurons. More recently, analysis of mRNA extracted from dysplastic tissue has revealed altered expression of NMDA and GABAA receptor subunits (3).

There are fewer electrophysiological than immunohistochemical studies on human dysplastic tissue, which perhaps is because of the difficulties in obtaining live tissue and suitable controls. Studies on cellular physiology in human tissue offer a unique set of challenges. It currently is unclear whether the “epileptogenic zone” needs to be defined as the area of dysplastic tissue or the area of spiking and seizure onset, as determined by surface electrocorticography. Some studies suggest that seizures are generated by dysplastic tissue and then propagated to surrounding normally laminated tissue, whereas others suggest that they arise from normally laminated tissue around the dysplatic tissue. Calcagnotto et al. defined the actively spiking region within the dysplasia as the epileptogenic zone. The authors did not clarify whether the experimental tissue included any nondysplastic surrounding tissue that demonstrated spiking, nor did they provide outcome data on their patients. Thus, if the “epileptogenic zone” was removed in 17 patients with focal cortical dysplasia, they should have become seizure free or experienced a significant reduction in seizure frequency. If a patient continues to have seizures after surgery, the resected tissue may or may not have contained critical parts of the seizure network. Control tissue used in this study was lateral temporal neocortex resected during temporal lobe epilepsy surgery. This approach has limitations because temporal neocortex may differ in significant ways from frontoparietal neocortex, which is also a site of focal cortical dysplasia.

An electrophysiologist can sample only a small number of neurons out of thousands present in resected tissue. Calcagnotto et al. studied pyramidal cells in the dysplastic cortex. The pyramidal neurons are large output neurons that can generate bursts, and synchronization and propagation of these bursts can generate seizures. In contrast to this study, Cepeda and colleagues studied cytomegalic neurons cells and balloon cells in generating epileptiform discharges (4). Calcagnotto et al. found that there was a reduced frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from pyramidal cells in dysplastic tissue compared to those recorded from pyramidal cells in control tissue. The authors suggested that this reduced inhibition of pyramidal neurons could increase the propensity for seizures. Pyramidal neuron IPSCs are generated by phasic release of GABA from presynaptic terminals of GABAergic interneurons; therefore, one would expect a reduction in interneurons or their terminals in the dysplastic tissue. Surprisingly, the total number of interneurons within the dysplastic tissue was not different from the control tissue. However, the interneurons appeared to be maldistributed in dysplastic tissue. In the normal cortex, calbindin- and parvalbumin-containing interneurons are restricted to layer II/III of the cortex, but these neurons were widely distributed in dysplasia. Interestingly, studies in an animal model of dysplasia (in utero exposure to radiation) also demonstrated sIPSC reduced frequency (5). These studies offer an exciting new hypothesis that disordered migration of interneurons within the dysplastic tissue contributes to the pathogenesis of seizures.

Further advances in understanding disorders of migration of interneurons require a consistent system of classifying interneurons and a mechanistic understanding of birth and migration of individual subtypes of interneurons. GABAergic interneurons in the cerebral cortex are diverse, and the number of classification systems appears to exceed the varieties of interneurons. Interneurons can be classified based on phenotypic features, such as size, shape, and orientation of cell soma; dendritic branching topology; presence or absence of spines; axonal features, such as myelinated or unmyelinated; and presence or absence of gap junctions. Similarly, molecular schemes (one of which Calcagnotto et al. used in their study) classify interneurons based on expression of transcription factors; calcium binding proteins, such as calbindin and parvalbumin; or neuropeptides, such as somatostatin and cholecystokinin. Another set of classifications can be generated on the basis of the physiological properties of interneurons. These atomized classification schemes make it difficult to compare results between studies and between different techniques. Some recent studies have begun to clarify the picture by characterizing as many features of interneurons as possible and then placing them into overlapping classes (6).

Over the last decade tremendous progress has been made in understanding the source and migration of cortical interneurons. Early fate mapping experiments revealed that cortical interneurons are generated in the ventricular zone of the ventral ganglionic eminences and migrate tangentially into developing cortex. By contrast, pyramidal neurons are generated in the cortical subventricular zone and migrate in radial fashion. There is growing evidence to suggest that distinct sets of interneurons are specified in three ganglionic eminences: medial, lateral, and caudal. The place and time of origin of interneurons appears to determine their phenotypic destiny (7). Abnormal electrical activity could arise in dysplastic tissue if a class of interneurons fails to migrate into the dysplastic tissue. Alternately, dysplasia may be a barrier to the migration of interneurons, with surrounding tissue potentially being deprived of inhibitory neurons. Interneuron fate mapping studies in animal models of cortical dysplasia could address these possibilities.


1. Bingaman WE. Surgery for focal cortical dysplasia. Neurology. 2004;62(suppl 3):S30–S34. [PubMed]
2. Najm I, Ying Z, Babb T, Crino PB, Macdonald R, Mathern GW, Spreafico R. Mechanisms of epileptogenicity in cortical dysplasias. Neurology. 2004;62(suppl 3):S9–S13. [PubMed]
3. Crino PB, Duhaime AC, Baltuch G, White R. Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia. Neurology. 56:906–913. [PubMed]
4. Cepeda C, Andre VM, Vinters HV, Levine MS, Mathern GW. Are cytomegalic neurons and balloon cells generators of epileptic activity in pediatric cortical dysplasia? Epilepsia. 2005;46(suppl 5):82–88. [PubMed]
5. Zhu WJ, Roper SN. Reduced inhibition in an animal model of cortical dysplasia. J Neurosci. 2000;20:8925–8931. [PubMed]
6. Toledo-Rodriguez M, Goodman P, Illic M, Wu C, Markram H. Neuropeptide and calcium-binding protein gene expression profiles predict neuronal anatomical type in the juvenile rat. J Physiol. 2005;567(Pt 2):401–413. [PubMed]
7. Butt SJ, Fuccillo M, Nery S, Noctor S, Kriegstein A, Corbin JG, Fishell G. The temporal and spatial origins of cortical interneurons predict their physiological subtype. Neuron. 2005;48:591–604. [PubMed]

Articles from Epilepsy Currents are provided here courtesy of American Epilepsy Society