Development and regulation of synaptic divergence in the mammalian retina

Thesis (Ph.D.)--University of Washington, 2019During neural development, neurons must not only contact the appropriate postsynaptic partners, but also form precise stereotypic patterns of connectivity, the characteristic number and distribution of synapses onto partners. These stereotypic patterns determine how and where information is processed within a circuit, and thus their proper development is critical to normal circuit function. While progress has been made in understanding the cellular and molecular mechanisms that match neurons with their synaptic partners and even to subcellular locations on these partners, it is not yet well understood how most neurons achieve their synaptic distribution patterns. Both cell-autonomous and non-cell autonomous mechanisms have been found to regulate the development of synapses from multiple distinct presynaptic cell types onto a common postsynaptic partner (convergence). However, it remains unknown how an individual neuron establishes synapses with multiple distinct cell types (divergence), especially when the distribution of synapses is unequal across partners. Therefore, the goal of my thesis was to determine the cellular strategies and mechanisms that underlie the development of synaptic divergence in a central nervous system (CNS) circuit. The retina is an excellent model system for studying the development of synaptic patterns because the compact and laminar organization of the cells and their connections makes all components of the circuit accessible for visualization and manipulation. Thus, I focused on the development of a retinal inhibitory circuit in which an interneuron (amacrine cell) connects to distinct postsynaptic cell types. In Chapter 1, I review what is known about the mechanisms underlying the development of synaptic patterns and inhibitory circuits in the CNS. I also briefly review the development of the vertebrate retina, the model system for my studies. In Chapter 2, I investigate the cellular strategies that shape the development of amacrine cell synaptic output patterning. In Chapter 3, I examine potential mechanisms that underlie the development of AII AC presynaptic structures and synaptic patterning described in Chapter 2. In Chapter 4, I summarize my findings and discuss future directions based on my findings thus far