Diversity in origin and migration of interneurons and their contribution to disease pathology

Evolutionary increase in complexity of cortical GABAergic network leads to significant variability in places of origin and routes of migration for GABAergic neurons. Here we present data from postmortem human and monkey fetal brain tissue processed for classical histological and immunohistochemical methods, with aim to identify their places of origin and their migratory routes. Our data confirmed that the ganglionic and septal eminence are the most important sources of GABAergic neurons. From these sources, they tangentially migrate through the subventricular and intermediate zone of the dorsal telencephalon (pallium). During the middle fetal period, significant production of GABAergic neurons also occurs in the pallial proliferative zones. The vast majority of the progenitors as well as migratory neurons from aforementioned sources strongly expressed GAD65 but not GAD67. Through early and middle fetal period numerous tangentially migrating cells within ganglionic eminence and lateral migratory stream were calretinin expressing cells. Intensive GAD67 expression was observed in a population of migratory cells that accumulates in the basal telencephalon and migrate to the pallium through the marginal zone and the layer under the cortical plate. These cells originate from, until now undescribed specific parts of the proliferative zones in the rostro-dorsal and caudal part of the medial telencephalic wall, proliferative zones between medial and lateral ganglionic eminence, hypothalamus and reticular thalamic nucleus. During middle fetal period they also originated from the proliferative zone at the top of the temporal lobe from where they enter into the marginal zone. Somatostatin positive migratory cells were densely packed in part of the zones where strong GAD67 reactive cells are found. Around mid-gestation, GAD65 positive small migratory like cells increased in number through marginal zone, forming 5-10 cells thick densely packed sublayer. By the end of middle trimester, lateral migratory stream was still massive and ganglionic eminence maintained its size. These data strongly support the view that important fraction of cortical GABAergic neurons is produced in the last trimester of gestation. Extended production, new sources and migratory routes of cortical GABA-ergic neurons participate to increased diversity of this cell population in the human cerebral cortex, but also makes them more prone to pathological alterations during development.