Our visual system operates over an astoundingly wide dynamic range that covers over 10 orders of magnitude, with light environments ranging from the near dark twilight to the bright noonday sun. Rod photoreceptors function over the lowest 8 orders of magnitude of our visual range and encode our most sensitive vision. In the mammalian retina, rod signals are relayed to a single class of rod bipolar cells (RBCs) and form the basis for the rod bipolar pathway. Adaptive processes are key to integrating rod photoresponses into the retinal circuitry and establishing the wide dynamic range of rod vision. Adaptation is known to occur both presynaptically in rods and postsynaptically in RBCs. However, the relative contribution of these mechanisms to adaptation is not clear.
Overall, my thesis projects explore the fundamental processes that modulate synaptic transmission in retinal circuits, particularly between rods and rod bipolar cells. I recorded light-evoked responses from rods and RBCs of wildtype and several transgenic mouse strains using single-cell patch clamp methods, and analyze response sensitivity under dark-adapted conditions and during light adaptation.
My first goal was to identify the molecular mechanisms responsible for the formation of rod-to-RBC synapses. In collaboration with the laboratory of Kirill A. Martemyanov (The Scripps Research Institute), we found that the rod-specific cell adhesion molecular ELFN1 interacts trans-synaptically with the postsynaptic receptor mGluR6 on RBC dendrites, and that this interaction is required for high-sensitivity vision of the rod pathway. We also found that the extracellular calcium channel CaV1.4 subunit α2δ4 forms complexes with ELFN1 and bridges presynaptic calcium channels to postsynaptic mGluR6 channels. Experiments in mice lacking α2δ4 reveal that this subunit is crucial for calcium-channel voltage sensitivity and rod-to-RBC synaptic transmission.
A key process in adaptation involves the movement of several signaling molecules in rod photoreceptors. One such molecule, the G-protein transducin, translocates to the rod inner segment and synaptic terminal in the light, and this process enhances synaptic transmission between rods and RBCs. Our next goal was to identify the mechanism of transducin modulation of rod-to-RBC signal transmission. In collaboration with the laboratory of Nikolai O. Artemyev (University of Iowa), we examined the functional role of the cargo protein UNC119, which is important for transducin translocation. We describe a novel function for UNC119 as an enhancer of synaptic transmission between rods and RBCs.
Lastly, I explored the biophysical mechanisms that control the responsiveness of RBCs over a wide range of light intensities. My preliminary data suggest that intracellular calcium acts on two targets in RBCs to increase the sensitivity and temporal resolution of RBC responses. This study is part of an ongoing effort in the lab.
Together, these projects provide insight into fundamental properties of signaling at the rod-to-RBC synapse, both presynaptically and postsynaptically, that permit the large dynamic range of rod vision.