The synapse between cones, horizontal cells and bipolar cells in the retina might be one of the most complex synapses in the vertebrate nervous system. At this synapse, the center/surround organization of bipolar cells is generated. The mechanism by which horizontal cells feed back to cones was, until recently, unresolved. In 1996 we showed that horizontal cells feed back to cones via modulation of the Ca2+-current in cones rather than a previously proposed GABAergic mechanism (Verweij et al., 1996, Vision Res.). A few years later we presented evidence that horizontal cells modulate the cone Ca2+-current via a connexin hemichannel mediated ephaptic mechanism (Kamermans et al., 2001, Science).
This is a unique form of synaptic transmission. Horizontal cell-activity modulates the extracellular potential within the synaptic cleft of the cone/horizontal cell synapse and in that way affects the cone Ca2+-current and thus glutamate release of the cones. This mechanism is almost noiseless, has no delay and is very fast. Many people confirmed our results. However, a competing hypothesis to account for the modulation of the Ca2+-current was put forward: the pH-hypothesis. In 2014 we showed that the complete feedback mechanism consists of an ultra‐fast ephaptic and a very slow ATP mediated component. ATP is released by horizontal cells via pannexin 1 channels Vroman et al., 2014, PLoS Biology). ATP is hydrolized in the synaptic cleft by ectoATPases which leads to the odulation of the pH in the synaptic cleft. We have generated animals that lack the critical components of this feedback system. With these animals we study the consequences of outer retinal inhibition retinal on information processing.
With morphological, molecular biological, electrophysiological and behavioral experiments we could confirm that connexin hemichannels and Pannexin 1 channels are mediating the negative feedback signal from horizontal cells to cones and showed that this feedback is essential for contrast enhancement. New biophysical experiments provided additional support for the ephaptic nature of this synaptic transmission. The feedback responses in cones have essentially the same time constance as the light responses of the horizontal cells driving the feedback pathway. The ATP mediated feedback component is very slow.
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