Migration and lineage of subventricular zone-derived cells that target the Islands of Calleja

Abstract

The subventricular zone (SVZ, also referred to as the subependymal layer; Boulder Committee, 1970) is a proliferative region that persists from neonate into adult. This region generates neurons that migrate via the rostral migratory stream into the olfactory bulb. However, in the neonate the SVZ also provides a second pathway of cells that migrate ventrally into the basal brain termed the ventral migratory mass (VMM) and form the basilar interneuron clusters called the Islands of Calleja (IOC). While neurogenesis and migration in the SVZ-RMS-OB has been well-documented, comparatively little is known of the development of SVZ-VMM-IOC. This study focuses on the development of the IOC, modulatory factors that affect VMM cell migration to the basal forebrain and reorganization into the islands, and potential heterogeneity amongst the interneurons targeting the IOC. Our results show formation of the IOC is almost completely a postnatal event, with the majority of islands and neurons forming within the first week postnatal (chapter 3). Furthermore, migration of the neurons contributing to the islands is modulated by GABA (chapter 4). Activation of GABAA receptors leads to an increase of migration rate and directional migration towards a point source of GABA observed under time-lapse confocal microscopy. Interestingly, this modulatory effect of GABA is opposite in the RMS where GABA agonists reduce migration. We observed that the GABAA receptors present in these two populations of neurons differed, which could underlie different response properties of these cells. Furthermore, disruption of GABA signaling in vitro disrupts cell reorganization into islands. Taken together this suggests a strong role for GABA in the formation of the IOC. In the SVZ-RMS-OB pathway SVZ-derived neuroblasts differentiate into several classes of interneurons in the OB, including calbindin-, calretinin-, neurocalcin-, and tyrosine hydroxylase-immunoreactive neurons. However, in the SVZ-VMM-IOC pathway the majority of neurons from SVZ (90%) become GABAergic interneurons with very few differentiating into any of the other interneuron classes (<1%). This observation that SVZ-derived progenitors targeting OB and IOC exhibit differential lineage potentiality suggests that there could be subpopulations of progenitor cells that are predetermined for each target tissue, or that there are strong environmental factors dictating differentiation in each location.