Article

Pyramidal cell responses to γ-aminobutyric acid differ in type I and type II cortical dysplasia

Mental Retardation Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Journal of Neuroscience Research (Impact Factor: 2.73). 11/2008; 86(14):3151-62. DOI: 10.1002/jnr.21752
Source: PubMed

ABSTRACT Abnormalities in the gamma-aminobutyric acid (GABA)-ergic system could be responsible for seizures in cortical dysplasia (CD). We examined responses of pyramidal neurons to exogenous application of GABA, as well as alterations of GABAergic interneuron number and size in pediatric epilepsy surgery patients with non-CD, type I CD, and type II CD pathologies. We used the dissociated cell preparation for electrophysiology along with immunohistochemistry to identify number and size of GABAergic cells. Pyramidal neurons from type I CD tissue showed increased EC(50) and faster kinetics compared with cells from non-CD and type II CD tissue. Cytomegalic pyramidal neurons showed increased GABA peak currents and decreased peak current densities, longer kinetics, and decreased sensitivity to zolpidem and zinc compared with normal pyramidal cells from non-CD and type I CD. There were fewer but larger glutamic acid decarboxylase (GAD)-containing cells in type II CD tissue with cytomegalic neurons compared with non-CD, type I CD, and type II CD without cytomegalic neurons. In addition, GABA transporters (VGAT and GAT-1) showed increased staining surrounding cytomegalic neurons in type II CD tissue. These results indicate that there are differences in GABA(A) receptor-mediated pyramidal cell responses in type I and type II CD. Alterations in zolpidem and zinc sensitivities also suggest that cytomegalic neurons have altered GABA(A) receptor subunit composition. These findings support the hypothesis that patients with type I and type II CD will respond differently to GABA-mediated antiepileptic drugs and that cytomegalic neurons have features similar to immature neurons with prolonged GABA(A) receptor open channel times.

0 Followers
 · 
154 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Seizure activities often originate from a localized region of the cerebral cortex and spread across large areas of the brain. The properties of these spreading abnormal discharges may account for clinical phenotypes in epilepsy patients, although the manner of their propagation and the underlying mechanisms are not well understood. In the present study we performed flavoprotein fluorescence imaging of cortical brain slices surgically resected from patients with partial epilepsy caused by various symptomatic lesions. Elicited neural activities in the epileptogenic tissue spread horizontally over the cortex momentarily, but those in control tissue taken from patients with brain tumors who had no history of epilepsy demonstrated only localized responses. Characteristically, the epileptiform propagation comprised early and late phases. When the stimulus intensity was changed gradually, the early phase showed an all-or-none behavior, whereas the late phase showed a gradual increase in the response. Moreover, the two phases were propagated through different cortical layers, suggesting that they are derived from distinct neural circuits. Morphological investigation revealed the presence of hypertrophic neurons and loss of dendritic spines, which might participate in the aberrant activities observed by flavoprotein fluorescence imaging. These findings indicate that synchronized activities of the early phase may play a key role in spreading abnormal discharges in human cortical epilepsies.
    NeuroImage 05/2011; 58(1):50-9. DOI:10.1016/j.neuroimage.2011.05.046 · 6.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The dorsal cochlear nucleus (DCN) is a brainstem structure that receives input from the auditory nerve. Many studies in a diversity of species have shown that the DCN has a laminar organization and identifiable neuron types with predictable synaptic relations to each other. In contrast, studies on the human DCN have found a less distinct laminar organization and fewer cell types, although there has been disagreement among studies in how to characterize laminar organization and which of the cell types identified in other animals are also present in humans. We have reexamined DCN organization in the human using immunohistochemistry to analyze the expression of several proteins that have been useful in delineating the neurochemical organization of other brainstem structures in humans: nonphosphorylated neurofilament protein (NPNFP), nitric oxide synthase (nNOS), and three calcium-binding proteins. The results for humans suggest a laminar organization with only two layers, and the presence of large projection neurons that are enriched in NPNFP. We did not observe evidence in humans of the inhibitory interneurons that have been described in the cat and rodent DCN. To compare humans and other animals directly we used immunohistochemistry to examine the DCN in the macaque monkey, the cat, and three rodents. We found similarities between macaque monkey and human in the expression of NPNFP and nNOS, and unexpected differences among species in the patterns of expression of the calcium-binding proteins. Anat Rec, 2014. © 2014 Wiley Periodicals, Inc.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 10/2014; 297(10). DOI:10.1002/ar.23000 · 1.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cortical dysplasia is the most common etiology in children and the third most frequent finding in adults undergoing epilepsy neurosurgery. The new International League Against Epilepsy (ILAE) classification grades isolated cortical dysplasia into mild type I (cortical dyslamination), severe type II (dyslamination plus dysmorphic neurons and balloon cells), and dysplasia associated with other epileptogenic lesions (type III). Multilobar type II lesions present at an earlier age and with more severe epilepsy compared with focal type I abnormalities, often in the temporal lobe, and these findings are reflected in types and age of operations for cortical dysplasia. Presurgical evaluation of patients with epilepsy from cortical dysplasia can be challenging. Interictal and ictal scalp electroencephalography (EEG) accurately localizes cortical dysplasia with 50-66% accuracy. Structural magnetic resonance imaging (MRI) is negative in roughly 30% of cases, most often linked with mild type I cases. FDG-PET can be 80-90% accurate, but is not 100% sensitive. Chronic intracranial electrodes are used in about 50% of cases with cortical dysplasia, but often do not capture restricted ictal-onset zones. About 60% of patients with cortical dysplasia are seizure free after epilepsy neurosurgery, with much higher rates of becoming seizure free with complete (80%) compared with incomplete (20%) resections. The most common reason for incomplete resection is the risk of an unacceptable neurologic deficit. Future challenges include better tools in identifying subtle forms of type I cortical dysplasia, and development of adjunctive treatments from basic research for those undergoing incomplete resections.
    Epilepsia 09/2012; 53 Suppl 4:98-104. DOI:10.1111/j.1528-1167.2012.03619.x · 4.58 Impact Factor