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Interneuron deficits in patients with the Miller-Dieker syndrome

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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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Authors and Affiliations

  1. Department of Pathology, Children’s Hospital of Pennsylvania and the University of Pennsylvania School of Medicine, Philadelphia, PA, 19104, USA

    MacLean Pancoast & Jeffrey A. Golden

  2. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA

    William Dobyns

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  1. MacLean Pancoast
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  2. William Dobyns
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  3. Jeffrey A. Golden
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Correspondence to Jeffrey A. Golden.

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Pancoast, M., Dobyns, W. & Golden, J.A. Interneuron deficits in patients with the Miller-Dieker syndrome. Acta Neuropathol 109, 400–404 (2005). https://doi.org/10.1007/s00401-004-0979-z

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  • DOI: https://doi.org/10.1007/s00401-004-0979-z

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