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Cerebral Cortex Advance Access published online on February 20, 2009
Cerebral Cortex, doi:10.1093/cercor/bhp009
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© The Author 2009. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Selective Depletion of Molecularly Defined Cortical Interneurons in Human Holoprosencephaly with Severe Striatal Hypoplasia

Sofia Fertuzinhos1,2, Zeljka Krsnik1, Yuka Imamura Kawasawa1, Mladen-Roko Rasin1, Kenneth Y. Kwan1, Jie-Guang Chen1, Milos Judas3, Masaharu Hayashi4 and Nenad Sestan1

1 Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA, 2 Doctoral Program in Experimental Biology and Biomedicine, University of Coimbra, 3004-517 Coimbra, Portugal, 3 Croatian Institute for Brain Research, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia, 4 Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Tokyo 183-8526, Japan

Address correspondence to Nenad Sestan, Department of Neurobiology, Yale University School of Medicine, PO Box 208001, New Haven, CT 06520-8001, USA. Email: nenad.sestan{at}yale.edu.

Cortical excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons follow substantially different developmental programs. In rodents, projection neurons originate from progenitors within the dorsal forebrain, whereas interneurons arise from progenitors in the ventral forebrain. In contrast, it has been proposed that in humans, the majority of cortical interneurons arise from progenitors within the dorsal forebrain, suggesting that their origin and migration is complex and evolutionarily divergent. However, whether molecularly defined human cortical interneuron subtypes originate from distinct progenitors, including those in the ventral forebrain, remains unknown. Furthermore, abnormalities in cortical interneurons have been linked to human disorders, yet no distinct cell population selective loss has been reported. Here we show that cortical interneurons expressing nitric oxide synthase 1, neuropeptide Y, and somatostatin, are either absent or substantially reduced in fetal and infant cases of human holoprosencephaly (HPE) with severe ventral forebrain hypoplasia. Notably, another interneuron subtype normally abundant from the early fetal period, marked by calretinin expression, and different subtypes of projection neuron were present in the cortex of control and HPE brains. These findings have important implications for the understanding of neuronal pathogenesis underlying the clinical manifestations associated with HPE and the developmental origins of human cortical interneuron diversity.

Key Words: basal ganglia • brain evolution • cerebral cortex • developmental disorder • interneuronopathy • nitric oxide


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