The retina contains ~100 neuronal cell types, each of which contribute to visual processing by wiring together in distinct parallel circuits. The point of convergence for circuit determination resides in the inner plexiform layer (IPL) of the retina, where axons and dendrites from ganglion cells, bipolar cells, and amacrine cells coalesce to form a synaptic neuropil containing 10 distinct sublayers. Neurons belonging to the same circuit stratify distinct sublayers of the IPL to make circuit specific synaptic connections. The cellular and molecular cues that direct development of these layers are largely unknown but crucial to determining which neurons wire together. The objective of this application is to determine the developmental mechanisms that enable the formation of one specific circuit, the direction selective (DS) circuit. My central hypothesis is that starburst amacrine cells (SACs) create and organize the DS circuit, through interactions among themselves as well as with the arbors of other DS circuit cell types. The rationale for this work is that the DS circuit is not only of great importance to understanding organization of the IPL, but understanding how the DS circuit forms will elucidate the mechanisms used by circuits throughout the CNS. I have formulated two specific aims that will directly test my central hypothesis.
Aim 1) Determine the mechanisms that initially create the DS circuit IPL sublayers. Our preliminary data suggests that SAC-SAC homotypic contact prompts stratification of the IPL. When MEGF10, a cell-surface molecule known to mediate SAC homotypic recognition, is removed, assembly of the circuit is delayed.
Aim 2) Determine the mechanisms that recruit DS ganglion and bipolar cells to the DS layers of the IPL. We have discovered a mouse line that has SAC IPL projection errors. This unique tool enables me to determine if SACs recruit their synaptic partners, DS-circuit ganglion and bipolar cells, to the DS IPL sublayers. Together, these two aims will reveal the cellular and molecular mechanisms SACs use to initially stratify the IPL and direct assembly of the other DS cell types. The knowledge we gain from this study will contribute to our understanding of the mechanisms neurons in the CNS use to form cell type specific connections and will further our understanding of how the IPL develops. A thorough understanding of these processes will be required to eventually repair neural circuits after disease or injury.
STATEMENT The mechanisms that guide circuit specific wiring in the central nervous system are largely unknown. This application seeks to identify the molecular and cellular mechanisms that direct assembly of the retinal direction selective circuit.
| Ray, Thomas A; Roy, Suva; Kozlowski, Christopher et al. (2018) Formation of retinal direction-selective circuitry initiated by starburst amacrine cell homotypic contact. Elife 7: |
