Neurology -- Correspondence for Crino et al., 56 (7) 906-913

Correspondence published:

Reply to Roesler et al.: Peter B Crino (9 August 2001)

Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia: R Roesler, "R L D Machado, J Quevedo" (9 August 2001)

Reply to Roesler et al. 9 August 2001

Peter B Crino
University of Pennsylvania Medical Center
Send Correspondence to journal:
Re: Reply to Roesler et al.

crinop{at}mail.med.upenn.edu Peter B Crino

We appreciate the thoughtful hypothesis proposed by Roesler et al. regarding the potential role of glutamate and GABA-A receptor subunit gene changes in cognitive deficits associated with human focal cortical dysplasia (FCD). Clearly, glutamate receptor subunits play critical roles in the establishment of long-term potentiation (LTP), a mechanistic process that is central to learning and memory and altered expression of glutamate and GABA receptor subunits are associated physiologically with hyperexcitability, excitotoxicity, and neurodegeneration and manifested clinically by seizures, mental retardation, and dementia.
While the changes in receptor subunit confirmation identified in dysplastic neurons may reflect selective alterations in gene transcription that result in intractable seizures observed in many FCD patients, a compelling hypothesis is expression changes in these receptors may also contribute to neuropsychiatric abnormalities such as autism or mental retardation that exist as co-morbid conditions in a variety of cortical dysplasia syndromes. [1] Many individuals with FCD do not exhibit cognitive deficits and in fact, some do not have epilepsy. However, among those patients who suffer seizures and mental retardation related to FCD, a central unresolved issue is the impact that the pharmacologic and structural abnormalities characteristic of FCD has on neuropsychiatric function. The current view is that FCD represents an "island" of aberrant cortical cytoarchitecture surrounded by a "sea" of normal cortex. [2, 3, 4]. In fact, we are just beginning to understand the ramifications of abnormal synaptic connectivity in FCD [5, 6, 7] and how this may directly affect the physiology of adjacent and putatively "normal" cortex. Indeed, the functional effects of FCD may extend beyond what is identified as histologically abnormal and this may also account for cognitive deficits in these patients. Conversely, a penumbra of cortical microdysgenesis may extend beyond the outer borders of a focal dysplasia which further compromises function of that cortical region. An important future study will be to assess the expression of glutamate and GABA receptor subunits in adjacent non-dysplastic cortex, as well as, in subcortical structures in patients with FCD, epilepsy, and cognitive deficits to determine whether more pervasive alterations of these receptors occurs beyond the border of the dysplasia and may contribute to cognitive deficits in FCD.
References:
1) Schwartzkronin PA, Walsh CA. Cortical malformations and epilepsy. Ment Retard Dev Disabil Res Rev 2000; 6:268-280.
2) Mischel P, Nguyen L. Vinters H. Cerebral cortical dysplasia associated with pediatric epilepsy. Review of neuropathologic features and proposal for grading system. J Neuropath and Exp Neurol 1995; 54:137-153.
3) Crino PB, Eberwine J. Cellular and molecular basis of cerebral dysgenesis. J Neurosci Res 1997; 50:907-916.
4) Rorke, L. A perspective: The role of disordered genetic control of neurogenesis in the pathogenesis of migration disorders. J Neuropath Exp Neurol 1994; 53: 105-117.
5) Jacobs KM, Kharazia VN, Prince DA. Mechanisms underlying epileptogenesis in cortical malformations. Epilepsy Res 1999; 36:165-188.
6) Avoli M, Bernasconi A, Mattia D, Olivier A, Hwa GG. Epileptiform discharges in the human dysplastic neocortex: In vitro physiology and pharmacology. Ann Neurol 1999; 46: 816-826.
7) Luhmann HJ, Karpuk N, Qu M, Zilles K. Characterization of neuronal migration disorders in neocortical structures. II. Intracellular in vitro recordings. J Neurophysiol 1998; 80:92-102.

Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia 9 August 2001

R Roesler
Universidade do Extremo Sul Catarinense Criciuma Brazil,
"R L D Machado, J Quevedo"
Send Correspondence to journal:
Re: Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia

rafaelroesler{at}hotmail.com R Roesler, et al.

Using a single-cell molecular biology approach to analyze glutamate and -aminobutyric acid A (GABAA) receptor subunit mRNA, Crino et al.[1] showed cell specific changes in the expression of N-methy-D- aspartate (NMDA) and GABAA receptor subunit mRNA in dysplastic and heterotopic neurons from six cases of human focal cortical dysplasia (FCD). An important point raised by these findings is that the abnormal expression of NMDA and GABAA receptor subunit mRNA described by Crino et al.1 might be the mechanistic basis for cognitive deterioration associated with cortical dysplasia. [2]
Both NMDA and GABAA receptors are importantly involved in learning and memory processes. Animal studies have shown that changes in the expression of glutamate receptor subunits are involved in the mechanisms underlying cognitive impairment. Thus, prenatal treatment with the antimitotic drug methylazoxymethanol induces both cortical dysplasia and cognitive deficits associated with a reduced expression of the NR1 subunit and increased GluR2 subunit mRNA in rats. [3]
Moreover, it has been recently shown aged rats exhibit a reduced expression in the NR2B subunit mRNA associated with deficits in long-term potentiation (LTP), learning and memory, [4] and rats chronically exposed to lead show deficits in spatial learning and LTP associated with reduced expression of NR1 and NR2A subunit mRNA in the hippocampal dentate gyrus. [5] Together with human studies suggesting an association between cortical dysplasia, cognitive deficits and dementia, [2] the findings from animal studies support the hypothesis that the receptor gene transcription changes observed by Crino et al.[1] in cortical dysplasia might be involved in mediating cognitive deficits in FCD patients.
References:
1. Crino PB, Duhaime AC, Baltuch G, White R. Differential expression of glutamate and GABA-A receptor subunit mRNA in cortical dysplasia. Neurology 2001;56:906-913.
2. Oki J, Miyamoto A, Takahashi S, Takei H. Cognitive deterioration associated with focal cortical dysplasia. Pediatr Neurol 1999;20:73-77.
3. Rafiki A, Chevassus-au-Louis N, Ben-Ari Y, Khrestchatisky M, Represa A. Glutamate receptors in dysplastic cortex: an in situ hybridization and immunohistochemistry study in rats with prenatal treatment with methylazoxymethanol. Brain Res 1998;782:142-152.
4. Clayton DA, Browning MD. Deficits in the expression of the NR2B subunit in the hippocampus of aged Fisher 344 rats. Neurobiol Aging 2001:22:165-168.
5. Nihei MK, Desmond NL, McGlothan JL, Kuhlmann AC, Guilarte TR. N- methyl-D-aspartate receptor subunit changes are associated with lead- induced deficits of long-term potentiation and spatial learning. Neuroscience 2000;99:233-242.