Cerebral Cortical Dysplasia: Giant Neurons Show Potential for Increased Excitation and Axonal Plasticity

Abstract

Cerebral cortical dysplasia (CD) is a common cause of intractable childhood epilepsy. Five cases of CD were analyzed for GABA_A receptor subunit β (GABA_Aβ), glutamate decarboxylase, AMPA receptor subunit 1 (GluR1) and subunit 2/3 (GluR2/3), and NMDA receptor 2 (NMDAR2) immunoreactivity. Antisera to the highly polysialylated neural cell adhesion molecule (PSA-NCAM) and human unc-33-like phosphoprotein 1 (hUlip 1) were used to identify neurons with ‘developmentally immature’ characteristics. Differences between CD and comparison tissue (n = 3) included: (1) prominent GABA_Aβ immunoreactivity of the cytoplasm of dysmorphic neurons in the subcortical white matter and cortex in 1 CD case; (2) increased immunolabeling with anti-GluR1 and GluR2/3 antisera in dysmorphic neurons compared with more normal-appearing adjacent neurons and neurons from nondysplastic cortex; (3) varying numbers of cortical dysmorphic neurons stained for NMDAR2 in all 5 CD cases, in contrast to a complete lack of cellular immunoreactivity in 2/3 of the cases of nondysplastic cortex; (4) PSA-NCAM and hUlip 1 expression (usually observed only in populations of neurons that undergo axonal growth) was observed in CD tissue, but not in normal brain tissue. In summary, dysmorphic neurons in cases of CD have increased immunoreactivity for several excitatory neurotransmitter receptor subunits, show variable immunoreactivity for GABA_Aβ and show expression of several proteins that are normally expressed only in immature neurons or those with the potential for synaptic plasticity.

Pediatric Cortical Dysplasia: Correlations between Neuroimaging, Electrophysiology and Location of Cytomegalic Neurons and Balloon Cells and Glutamate/GABA Synaptic Circuits

“…For example, qualitative immunocytochemical studies using indirect markers of GABAergic neurons (e.g., calretinin, calbindin and parvalbumin) or mRNA levels of GABA A receptor subunits from CD tissue have reported decreased numbers of inhibitory neurons or differential expression of GABA A receptor subunits, suggesting the potential of reduced inhibition [Crino et al, 2001;Spreafico et al, 1998Spreafico et al, , 2000Thom et al, 2003]. Other studies have reported changes in glutamate receptor subunit protein and mRNA expression in CD tissue, supporting the concept that AMPA and NMDA excitatory functions may be enhanced [Crino et al, 2001;Kerfoot et al, 1999;Najm et al, 2000;Ying et al, 1998]. Our synaptic frequency data from normalpyramidal and cytomegalic neurons initiate the process of understanding alterations in glutamate and GABAergic synaptic properties in pediatric CD.…”

“…This hypothesis is supported by circumstantial anatomic and correlative electrocorticography (ECoG) studies demonstrating an association between the presence of dysmorphic cells with interictal and ictal abnormalities in CD patients [Boonyapisit et al, 2003;Palmini, 2000;Rosenow et al, 1998;Spreafico et al, 1998;Tassi et al, 2001]. Similarly, in CD tissue investigators have noted a qualitative reduction in GABAergic neurons and changes in the coassembly of AMPA, NMDA and GABA A receptor subunits in and around human dysplastic lesions, suggesting the possibility of enhanced excitation and partial loss of inhibition leading to seizures [Crino et al, 2001;Kerfoot et al, 1999;Mikuni et al, 1999;Najm et al, 2000;Ying et al, 1998]. …”

Cortical Dysplasia, Genetic Abnormalities and Neurocutaneous Syndromes

“…Ying et al [63] have found that hyperexcitability of dysplastic regions may result, in part, from the presence of NMDAR2 subunits and selectively expressed NMDAR1 splice variants in dysplastic neurons (see also the article by Kerfoot et al [64]). Direct electrophysiologic recordings from 'dysmorphic/bizarre' neuroglial cells in corticectomy specimens will also be valuable in assessing their potential contribution to seizure genesis.…”

Neuropathogical features of a rat model for perinatal hypoxic‐ischemic encephalopathy with associated epilepsy

“…Comparable findings have been described in cortical tissue resected from patients diagnosed with intractable epilepsy secondary to cortical dysplasia (Ferrer et al, 1992; AlonsoNanclares et al, 2004). Cytomegalic neurons and large cells with atypical morphology have been suggested to play an important role in the generation of epileptic activity due to their abnormal electrophysiological properties (Kerfoot et al, 1999;Cepeda et al, 2003). …”