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Origin of GABAergic neurons in the human neocortex


The mammalian neocortex contains two major classes of neurons, projection and local circuit neurons1,2,3,4. Projection neurons contain the excitatory neurotransmitter glutamate, while local circuit neurons are inhibitory, containing GABA2,4. The complex function of neocortical circuitry depends on the number and diversity of GABAergic (γ-aminobutyric-acid-releasing) local circuit neurons1,2,3. Using retroviral labelling in organotypic slice cultures of the embryonic human forebrain, we demonstrate the existence of two distinct lineages of neocortical GABAergic neurons. One lineage expresses Dlx1/2 and Mash1 transcription factors, represents 65% of neocortical GABAergic neurons in humans, and originates from Mash1-expressing progenitors of the neocortical ventricular and subventricular zone of the dorsal forebrain. The second lineage, characterized by the expression of Dlx1/2 but not Mash1, forms around 35% of the GABAergic neurons and originates from the ganglionic eminence of the ventral forebrain. We suggest that modifications in the expression pattern of transcription factors in the forebrain may underlie species-specific programmes for the generation of neocortical local circuit neurons5,6,7,8,9,10,11 and that distinct lineages of cortical interneurons may be differentially affected in genetic and acquired diseases of the human brain.

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Figure 1: Mode of migration of GABAergic neurons in the fetal human neocortex.
Figure 2: Mash1-expression in neocortical GABAergic neurons and VZ/SVZ progenitors.
Figure 3: Neocortical lineage of GABAergic neurons and their progenitors revealed by a retroviral analysis in living slices.
Figure 4: Neocortical GABAergic neurons originating in the GE.

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We thank J. E. Johnson for providing Mash1 antibodies and J. L. R. Rubenstein and S. Anderson for providing Dlx1/2 antibodies. We also thank F. Miller for providing Ta1-LacZ plasmid. We are grateful to all colleagues in the laboratory of P. R. for their advice and comments on the manuscript.

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Correspondence to Pasko Rakic.

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Letinic, K., Zoncu, R. & Rakic, P. Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649 (2002).

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