This study addresses the relationship between the elaborate structure of the mammalian cone photoreceptor synapse and signaling in postsynaptic bipolar cell retinal pathways that are critical for visual perception. Cone photoreceptors mediate vision under conditions of bright illumination and use glutamate as their transmitter. A cone contacts two functional classes of bipolar cells, On and Off, which have different glutamate receptors that cause them to depolarize (ie, signal) either at light-on or light-off, respectively. Each functional class of bipolar cell is further divided into 5-6 anatomical types (cb1a/b, b2, cb3a/b, for Off bipolar cells). Recent work has shown that the different anatomical subtypes of Off bipolar cells express different glutamate receptors (AMPA or kainate), contact the cone terminal at distinct distances from transmitter release sites (within invaginations or at the terminal base) and make different numbers of contacts with a cone terminal. The differences in transmitter diffusion distance, contact number, and receptor type suggest that each type of Off bipolar cell is specialized to carry a different component of the cone signal to the ganglion cells of the inner retina. The first aim addresses the impact of contact number on signaling during conditions of steady illumination. The basic idea is that vesicle fusion at each of a cone’s 20-40 synaptic ribbons is probabilistic, with a mean rate set by membrane voltage. Off bipolar cells make different numbers of contacts with a cone terminal, varying from 2- 15 depending on the type. The first aim will use simultaneous cone and Off bipolar cell recording to test key ideas about resampling of the cone signal at the synapse. Experiments will determine the fraction of a cone’s ribbon sites sampled by each bipolar cell type, and test the idea that the more ribbons a bipolar cell samples, the more accurate is its estimate of the cone signal. Experiments will also determine whether individual contacts at the base of the terminal sample more ribbons than contacts within invaginations, and assess the impact of contact placement on signaling accuracy. The combination of basal and invaginating contacts is unique to cones, and their respective functions in vision are poorly understood. The second aim examines the mechanisms of signaling at light-off, which also differs among the Off bipolar cell types. Cone depolarization at light-off produces a synchronous fusion of vesicles. We hypothesize that cone synapses with cb2 cells saturate during synchronous fusion, providing a mechanism to enhance rapid signaling of change within the visual scene. The ability to rapidly signal change can have utility for survival. We also hypothesize that cb1a cells make specialized contacts with cones that have a threshold non-linearity. In the cb1a cell pathway, sensitive signaling is traded-off for noise immunity. Specific experiments will determine the mechanisms of transient signal enhancement at the cone to cb2 cell synapse and the threshold non-linearity at the cone to cb1a cell synapse.
|Effective start/end date||3/1/14 → 2/28/18|
- Kennedy Institute - National Eye Clinic (5R01EY012141-20 REVISED)