Interneuron deficits in patients with the Miller-Dieker syndrome.
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.
Pancoast
MacLean
M
Department of Pathology, Children's Hospital of Pennsylvania and the University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Dobyns
William
W
Golden
Jeffrey A
JA
D000704:Analysis of Variance; D001921:Brain / Q000473:pathology*; D037282:Calreticulin / Q000378:metabolism; D016022:Case-Control Studies; D002452:Cell Count / Q000379:methods; D002648:Child; D002675:Child, Preschool; D005333:Fetus; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007395:Interneurons / Q000378:metabolism / Q000473:pathology*; D009421:Nervous System Malformations / Q000378:metabolism / Q000473:pathology*
D037282:Calreticulin