The long-term objective of this proposal is to contribute to understanding the development of the mammalian cerebral cortex. Specifically, we focus on GABA as a """"""""developmental neurotransmitter"""""""" and propose to study the development of sensitivity to GABA in cortical interneurons as they migrate tangentially from the ventral telencephalon to their destined positions in the cortex. The overriding hypothesis is that the tangentially migrating cells are heterogeneous and dynamic in their response profiles to GABA as well as expression of GABAA receptor subunits, and that these dynamic properties reflect their migratory disposition that is subject to regulation by extrinsic cues. There is now abundant evidence that GABA-containing cortical interneurons originate in the ganglionic eminence (GE) and follow tangential migratory routes to enter the cortex. GE-derived cells at the onset of corticogenesis populate the marginal zone (layer 1) while later generated cells enter the lower intermediate zone. However, little is known about their functional development of tangentially migrating neurons. In this project, we ask: (1) At what points along their migratory routes do tangentially migrating cells acquire sensitivity to GABA? (2) Do tangentially migrating cells display different response profiles to GABA and do they express different GABAA receptor subunits? (3) Are these differences related to the histogenetic origins, immunohistochemical identities of tangentially migrating cells? (4) Does GABA regulate tangential migration during cortical development? (5) Does the mechanism involve activation of GABA receptors expressed by tangentially migrating cells and ambient levels of GABA in the extracellular milieu? (6) Is the expression of GABAA receptors programmed intrinsically or is it influenced by factors that regulate tangential migration? Interest in neuronal migration has never been greater, as recent investigations have implicated migration abnormalities in several naturally occurring genetic defects in humans. Answers to the above questions will contribute toward elucidating many outstanding and pressing issues about tangential migration, the development of cortical interneuons and cortical development in general. ? ?
