Interneuron deficits in patients with the Miller-Dieker syndrome |
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Authors: | MacLean Pancoast William Dobyns Jeffrey A. Golden |
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Affiliation: | (1) Department of Pathology, Childrens Hospital of Pennsylvania and the University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA;(2) Department of Human Genetics, University of Chicago, Chicago, Illinois, USA |
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Abstract: | Lissencephaly is characterized by a thickened cortex and loss of gyri, resulting in the brain having a smooth surface. Patients with lissencephaly frequently exhibit epilepsy and mental retardation, conditions often associated with a defect in inhibitory neurons. While lissencephaly has traditionally been considered a disorder of radial migration, recent data indicate interneurons migrate non-radially, while projection neurons migrate radially. To determine if an interneuron defect, and therefore a non-radial migration defect, exists in patients with lissencephaly, we studied the calretinin-expressing interneuron subpopulation in the brains from two fetuses and two children with lissencephaly and a deletion involving 17p13 deletion (Miller-Dieker syndrome) along with age-matched controls. Our data indicate fetuses with the Miller-Dieker syndrome have a significant (tenfold) reduction in the number of calretinin-expressing interneurons present, whereas minimal reductions in the number of calretinin-expressing interneurons are present in children with this disorder. These data parallel those seen in the Lis1+/– mouse model of human lissencephaly, and are consistent with a non-radial cell migration defect in humans. Thus, when considering the pathogenesis of human lissencephaly and the clinical manifestations in these patients, defects in both non-radial cell migration (inhibitory interneurons) and radial migration (excitatory projection neurons) must be considered. |
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Keywords: | Interneuron Lissencephaly Miller-Dieker syndrome Calretinin Radial and non-radial cell migration |
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