Selective Transmission of Single Photon Responses by Saturation at the Rod-to-Rod Bipolar Synapse

{{Summary
 * title=Selective Transmission of Single Photon Responses by Saturation at the Rod-to-Rod Bipolar Synapse
 * authors=Alapakkam P. Sampath, Fred Rieke
 * url=http://www.cns.nyu.edu/csh/csh04/Articles/Sampath2004.pdf
 * tags=single photon response, rods, mouse
 * summary=Rod cells work remarkably well in the dark. One of the observed facets of this is a threshold-like nonlinear response of the retina to signals from each rod before combining them.  This series of experiments probes the mechanisms of that nonlinearity in mouse rods and comes up with a model that explains it in part in terms of synapse saturation, then explores that model in detail to see how well it matches observations.

Goals and Methods
A few mechanisms for nonlinear response to rod signals had been considered, but not explored in detail. Evidence for and against saturation at central nervous system synapses has been debated in different contexts, with some contemporary work suggesting some synapses are saturated at a single action potential but not otherwise. And more than one mechanisms is implicated in saturation.

This experiment aimed to identify whether saturation occured in rod transmission, and if so which mechanisms were involved, and whether this sufficed to account for the overall nonlinear response to rod signals in the mouse retina. Some reasons to focus on the rod-to-rod bipolar synapse include:
 * Rods are known to continuously release transmitter in the dark, slwoing down when hyperpolarized by light.
 * Receptor activity leads to closing nonselective cation channels through some sort of signal cascade, which could provide another source of saturation.
 * The ribbon-type synapses between rods and rod biploars involve small graded changes in voltage.

The light response of mouse rod bipolars was known to have a supralinear dependence on the strength of a flash, coming from the transfer of signal from rod to rod bipolar cell. This was investigated to see whether it was an intrinsic feature of the synapse or due to feedback from horizontal or amacrine cells.

Both voltage-clamped and perforated-patch methods were used to study and record signals from rod bipolar cells. The nonlinearity of the cell's response was estimated by the Hill exponent of the best fit to the flash strangth-response relation.

In one experiment, they were observed while subject to a range of flash intensities, both with and without suppressing the activity of nearby amacrine and horizontal cells.

In the dark, the rod bipolar transduction cascade was found to operate near saturation. But what was being saturated? Various tests for saturation were carried out : adding G protein; reducing the number of available receptors or stimulating them.

Results and Analysis
Most of the nonlinearity was accounted for by the effects of saturating the rod-to-rod bipolar synapse, rather than competing theories about feedback from nearby horizontal or amacrine cells.

Saturation was found to make the rod current insensitive to small changes in transmitter concentration around the rod. But what was saturated in the dark?


 * Adding G protein had little effect on the cascadee. It was more sensitive to decreases in G protein activity (as is produced by light).
 * Increasing receptor activity with APC increased its nonlinearity.  Decreasing receptor activity with LY341495 decreased its nonlinearity.   Since thse both unbind slowly, their influence on the response suggests the receptors themselves are not strongly saturated; this happens downstream.
 * Few transduction channels (<2 per rod) were found to be open, as estimated by single channel current and dark current fluctuations.

This saturation is in the G protein cascade that couples receptors to channels in rod bipolar dendrites, with little or no saturation of presynaptic or postsynaptic receptors. In the dark, 2 or fewer bipolar transduction channels are observed to be open at each synapse, compared to 30 at the peak of a single-photon response.

Two specific models are proposed, one produced by saturation directly at the transduction channels; the other produced in another component of the transduction cascade. Both could happen, but the results suggest they account for most of the nonlinearity.

Rods are known to be specialized for detecting single photons; this analysis highlights that the specialization may extend to specialized transfer of signals to rod bipolar cells.

Key references
G.D. Field, F. Rieke, Neuron 34 (2002)
 * Responses of retinal rods to single photons. D.A. Baylor, T.D. Lamb, K.-W. Yau, Journal of Physiology (1979)
 * Nonlinear signal transfer from mouse rods to bipolar cells and implications for visual sensitivity.
 * relevance=This work probed the mechanism of nonlinear responses of mouse rods in darkness, indicating that synapose saturation is the source of nonlinearity and suggesting where to look for the details of the saturation mechanism.

}}
 * journal=Neuron
 * pub_date=2004/02/05
 * doi=10.1016/S0896-6273(04)00005-4
 * subject=Neuroscience