According to a study conducted by Northwestern Medicine and published in Nature Communications, novel cellular mechanisms within the retina have been discovered. These findings have the potential to advance the development of targeted therapeutics for vision-related diseases and conditions.
The study focuses on cone synapses in the retina, which play a crucial role in processing changes in light. Steven DeVries, MD, Ph.D., the David Shoch, MD, Ph.D., Professor of Ophthalmology and senior author of the study, explains that cone synapses are unique because they have evolved to signal changes in light intensity.
DeVries states, "Counterintuitively, cone neurotransmitter release is high in the dark and reduced by light. When the light's brighter, the reduction is larger. When the lights are dimmer, it's smaller; it operates differently from most synapses which use an increase in transmitter release to signal all-or-nothing, digital action potentials."
Unlike other synapses in the brain, each individual cone synapse in the retina is connected to more than a dozen different types of post-synaptic neurons called bipolar cells. These bipolar cells relay information in parallel to the inner retina, contributing not only to conscious vision but also to subconscious processes like gaze stabilization.
The study conducted by the researchers involved non-human mammalian retinas. They utilized super-resolution microscopy to map out the locations of transmitter release sites, transmitter re-uptake proteins, and post-synaptic contacts at the cone synapse. The researchers employed a technique called "synaptic accounting" to establish a relationship between the amount of transmitter released by a cone and the responses in each post-synaptic bipolar cell type.
DeVries explains the unique nature of transmitter release at the cone synapse: "Transmitter is released in packets or quanta when a vesicle fuses with the presynaptic membrane. Since most synapses involve one-to-one direct contacts across a narrow cleft, it is assumed that one detected quantum equals one released quantum. The cone synapse has a different design that voids this assumption. We developed a way to stimulate a cone and count the vesicles that are released while at the same time counting the number of vesicles that are detected by the postsynaptic neuron."
By employing these techniques, the researchers demonstrated that certain bipolar cell types respond to individual fusion events and total quanta, while others respond to degrees of locally coincident events, leading to nonlinear summation. These differences are influenced by various factors specific to each bipolar cell type, including diffusion distance, contact number, receptor affinity, and proximity to transporters.
DeVries further explains, "The outer retina uses the same toolbox as elsewhere in the central nervous system, like vesicles, synaptic release zones, and postsynaptic receptors, but organizes these elements in novel ways to accomplish a different, very localized type of processing. Analog processing is also found in the dendritic tree of central nervous system neurons, where the bulk of calculation, both linear and nonlinear, occurs."
Moving forward, DeVries and his team plan to utilize a new, more powerful type of super-resolution microscopy to identify the protein components that constitute cone synapses. They also aim to determine the receptor responsible for the unique characteristics of the "strong signal" or high threshold bipolar cell that requires intense signals to respond.
In conclusion, the Northwestern Medicine study has shed light on novel cellular mechanisms within the retina, paving the way for advancements in targeted therapeutics for vision-related diseases and conditions.
Chad P. Grabner et al, Mechanisms of simultaneous linear and nonlinear computations at the mammalian cone photoreceptor synapse, Nature Communications (2023). DOI: 10.1038/s41467-023-38943-2