Retina Synapses Details are Discovered

According to data published in Nature Communications, a Northwestern Medicine study discovered unexpected cellular pathways within the retina, which could aid in the development of tailored therapies for diseases and conditions affecting vision.

Cone synapses within the retina of the eye assist the brain in processing changes in light. According to Steven DeVries, MD, Ph.D., the David Shoch, MD, Ph.D., Professor of Ophthalmology and senior author of the study, it is a unique synapse because it has evolved to transmit changes in light intensity.

“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,” DeVries said.

Unlike most other synapses in the brain, each cone synapse is linked to more than a dozen different types of post-synaptic neurons, known as bipolar cells, which transmit information to the inner retina in tandem. These parallel streams in the inner retina not only contribute to conscious vision but also to subconscious processes such as gaze stability.

The researchers used super-resolution microscopy to map out the locations of transmitter release sites, transmitter re-uptake proteins, and post-synaptic connections at the cone synapse in the current investigation, which involved non-human mammalian retinas. Then they used an approach called “synaptic accounting,” to relate the amount of transmitter released by a cone to the responses in each post-synaptic bipolar cell type.

“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,” DeVries said.

The researchers demonstrated that certain bipolar cell types respond to individual fusion events and total quanta, but others respond to degrees of locally coincident events, resulting in a nonlinear accumulation. These discrepancies are produced by a combination of bipolar cell-specific characteristics such as diffusion distance, contact number, receptor affinity, and proximity to transporters.

“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,” DeVries said.

According to DeVries, his team’s next step will be to use a new, more powerful sort of super-resolution microscopy to determine the protein components that make up cone synapses.

“One of the ways that the different bipolar cells divide the cone signal up is that some of them are very sensitive to small signals and others require strong signals to respond; the ‘strong signal’ or high threshold bipolar cell has a unique type of insensitive post-synaptic receptor. We would also like to identify this receptor,” DeVries said.

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