Origin of GABAergic neurons in the human neocortex

The mammalian neocortex contains two major classes of neurons, projection and local circuit neurons(1-4). Projection neurons contain the excitatory neurotransmitter glutamate, while local circuit neurons are inhibitory, containing GABA(2,4). The complex function of neocortical circuitry depends on the number and diversity of GABAergic (gamma-aminobutyric-acid-releasing) local circuit neurons(1-3). 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 neurons(5-11) and that distinct lineages of cortical interneurons may be differentially affected in genetic and acquired diseases of the human brain.