title: Selective depletion of molecularly defined cortical interneurons in human holoprosencephaly with severe striatal hypoplasia.
abstract: 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.
authors.affiliation: Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Fertuzinhos
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Krsnik
authors.forename: Yuka Imamura
authors.initials: YI
authors.lastname: Kawasawa
authors.forename: Mladen-Roko
authors.initials: MR
authors.lastname: Rasin
authors.forename: Kenneth Y
authors.initials: KY
authors.lastname: Kwan
authors.forename: Jie-Guang
authors.initials: JG
authors.lastname: Chen
authors.forename: Milos
authors.initials: M
authors.lastname: Judas
authors.forename: Masaharu
authors.initials: M
authors.lastname: Hayashi
authors.forename: Nenad
authors.initials: N
authors.lastname: Sestan
mesh_terms: D002540:Cerebral Cortex / Q000002:abnormalities* / Q000378:metabolism*; D003342:Corpus Striatum / Q000002:abnormalities* / Q000378:metabolism* / Q000473:pathology; D016142:Holoprosencephaly / Q000378:metabolism*; D006801:Humans; D007231:Infant, Newborn; D007395:Interneurons / Q000378:metabolism* / Q000473:pathology; D018377:Neurotransmitter Agents / Q000378:metabolism*
chemical_list: D018377:Neurotransmitter Agents