| Neural function relies upon the precise positioning of pre- and post-synaptic cells within structurally complex circuits. Although much is known about neuronal migration and synaptogenesis as distinct developmental events, it has been more difficult to synthesize an integrated view of how these characteristics develop within a single cell population. The laminar architecture and stereotypic synaptic relationships of the vertebrate retina facilitate this type of cell-focused approach, which I have applied to understanding the cellular positioning and laminar targeting of horizontal cells. Horizontal cell somata in the mature retina have a precise laminar position, and they also exhibit a nonrandom position relative to neighboring horizontal cells. Their lateralized dendritic and axonal arbors synapse with bipolar cell dendrites and the axonal terminals of photoreceptors in the outer plexiform layer (OPL). Static observations previously indicated that developing horizontal cells must undergo numerous positional and morphological changes to acquire their mature organization, but the cellular mechanisms underlying these changes are not fully understood. I examined the early development of horizontal cells in intact tissue by using a transgenic mouse line and time-lapse imaging. I found that horizontal cells use two distinct migratory modes, unconstrained radial migration and lateral somal translocation, to reach their final position. My observations also suggest a novel mechanism for cell patteming. Once horizontal cells reach the appropriate retinal depth, homotypic interactions between transient vertical processes maintain cell territories with minimal overlap. While homotypic interactions between vertical processes may help position horizontal cells, previous studies suggested that GABA release by these neurons affects the overall organization of the OPL. The pharmacological manipulations used by these studies, however, were nonspecific. I thus examined a conditional knockout mouse lacking glutamate decarboxylase 67 (GAD67), a GABA synthetic enzyme, and found that the OPL develops appropriately at the structural and cellular levels in the absence of GABA synthesis by horizontal cells. It remains possible, however, that the absence of GABA causes more subtle defects in synapse formation in the OPL. My studies of horizontal cell development therefore provide the first continuous view of how a single cell type becomes integrated into a circuit during development. |
