Synaptic Mechanisms in the Mammalian Retina

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

Our work focuses on specialized synapses in the mammalian retina. Many neurons in the retina communicate with each other over short distances without the need for action potentials. Instead, small light-evoked changes in membrane potential modulate an ongoing rate of synaptic vesicle release. Many of the synapses that mediate this "analog" signaling mode are distinguished by ribbon-like structures in their presynaptic terminals. Oriented orthoganally to the presynaptic membrane and tethered to dozens of synaptic vesicles, ribbons are thought to enable indefatigable vesicle release, but their exact role remains enigmatic. We hypothesize that these distinct presynaptic structures optimize analog signaling by ensuring a consistent relationship between presynaptic calcium channels and vesicle release sites. Our experiments now indicate that this hypothesis is wrong, and that a range of release probabilities exists among the docked vesicles at these synapses. Further experiments suggest that this heterogeneity may work together with the voltage-dependence of presynaptic Cav channels to enable this synapse to work over a wider dynamic range. This work is complete and is being written up for publication. In a collaborative project with researchers at the University of Nebraska and the Salk Institute, we have studied how the ultrastructure of rod photoreceptor synapses influences visual signaling. We reconstructed four complete rod spherules and incorporated the structures into realistic glutamate diffusion models using MCell. We find that the realistic synaptic geometry substantially prolongs the lifetime of synaptically released glutamate at the postsynaptic receptors on bipolar cells. This work was published this year (Thoreson, et al., 2025, J. Gen. Physiol.). In other experiments, we have employed electron microscopy and tomography on high-pressure frozen retinal tissue to examine the detailed structure of entire ribbon synapses at nanometer resolution. We have discovered that the population of synaptic vesicles at the base of the ribbon, previously considered to compose a homogeneous pool of readily releasable vesicles, actually occupy morphologically distinct states that may represent different stages in the vesicle priming process. This work has been submitted for publication, received favorable reviews, and is currently in the revision stage. Our studies of pathological activity in the rd10 mouse model of retinitis pigmentosa have given rise to several hypotheses regarding synaptic features that are altered during this process and potential therapies to alleviate synaptic and circuit dysfunction. Specifically, we have tested whether pathological depolarization of rod-driven bipolar cells diminishes signaling in the signaling pathway underlying night vision. Recording from retinal ganglion cells, we have found that reducing bipolar cell depolarization can reduce pathological oscillatory behavior with minimal impact on visual signaling. We have confirmed aspects of these results in in vitro electroretinograms (ERGs) and submitted a manuscript. In another collaborative effort, we are conducting electrophysiological experiments to confirm electron microscopic data showing ribbon synaptic connections from bipolar cell dendrites in the outer plexiform layer and horizontal cells. This work is ongoing.