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Origins and migratory routes of GABA-ergic neurons in the primate cerebral cortex

Gamma-Aminobutyric acidergic (GABAergic) neurons that correspond mainly to local circuit neurons play a crucial role in regulating the activity of cortical neuronal networks and the complex interactions among principal neurons. These functions depend on a very heterogeneous population of neurons, whose number and diversity may increase during mammalian evolution. Interestingly dysfunction and cell death of several specific types of GABAergic neurons is a hallmark of various psychiatric and neurological disorders such as schizophrenia, autism and epilepsies to which defect in genesis or migration of these neurons can be a predisposing factor. Understanding primate specific developmental mechanisms that regulate generation, migration and maturation of cortical GABA neurons, is a crucial step in elucidating such pathologies. However, there are few such studies in monkeys and humans, whereas they are numerous in lower mammals. In rodents, cortical GABAergic neurons are generated exclusively in the subcortical proliferative zone of the ventral telencephalon, the ganglionic eminence (GE), and migrate tangentially to the dorsal telencephalon to reach their target cortical layer. We reported (Petanjek et al. 2009, Cerebral Cortex 19:249-62) that in contrast to rodents, in cynomolgus monkey cortical GABAergic neurons are generated massively in the proliferative zones of the dorsal telencephalon, in addition to the GE. This neurogenesis occurs very early during brain development in both dorsal and ventral telencephalon but with distinct temporal profiles. GABAergic neuron progenitors labeled for transcription factor Mash1 and GABA synthesizing enzyme GAD65 were present mainly in the GE at embryonic days (E) 47-55, and in the entire dorsal telencephalon at E64-75. These progenitors within the dorsal telencephalon are generated locally rather than in the GE. In the human embryonic forebrain (Letinic et al. 2002, Nature 417:645-9) retroviral labeling in organotypic slice cultures also demonstrated 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 proliferative zones of the dorsal telencephalon. The second lineage, characterized by the expression of Dlx1/2 but not Mash1, forms in human brain only around 35% of the GABAergic neurons and originates from the GE of the ventral forebrain, in comparison to rodent where all GABAergic neurons originate in GE. The dorsal telencephalic origin of cortical GABA-ergic neurons is a unique feature of human and non-human primates and appears to be, in the primate lineage, an early evolutionary modification which provided increased number and variety of GABA-ergic neurons to an expanding neocortex.

GABA-ergic; neurons; primate; cortex; development

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