Abstract
BackgroundRecent studies designed to identify the mechanism by which retinal horizontal cells communicate with cones have implicated two processes. According to one account, horizontal cell hyperpolarization induces an increase in pH within the synaptic cleft that activates the calcium current (Ca2+-current) in cones, enhancing transmitter release. An alternative account suggests that horizontal cell hyperpolarization increases the Ca2+-current to promote transmitter release through a hemichannel-mediated ephaptic mechanism.Methodology/Principal FindingsTo distinguish between these mechanisms, we interfered with the pH regulating systems in the retina and studied the effects on the feedback responses of cones and horizontal cells. We found that the pH buffers HEPES and Tris partially inhibit feedback responses in cones and horizontal cells and lead to intracellular acidification of neurons. Application of 25 mM acetate, which does not change the extracellular pH buffer capacity, does lead to both intracellular acidification and inhibition of feedback. Because intracellular acidification is known to inhibit hemichannels, the key experiment used to test the pH hypothesis, i.e. increasing the extracellular pH buffer capacity, does not discriminate between a pH-based feedback system and a hemichannel-mediated feedback system. To test the pH hypothesis in a manner independent of artificial pH-buffer systems, we studied the effect of interfering with the endogenous pH buffer, the bicarbonate/carbonic anhydrase system. Inhibition of carbonic anhydrase allowed for large changes in pH in the synaptic cleft of bipolar cell terminals and cone terminals, but the predicted enhancement of the cone feedback responses, according to the pH-hypothesis, was not observed. These experiments thus failed to support a proton mediated feedback mechanism. The alternative hypothesis, the hemichannel-mediated ephaptic feedback mechanism, was therefore studied experimentally, and its feasibility was buttressed by means of a quantitative computer model of the cone/horizontal cell synapse.ConclusionWe conclude that the data presented in this paper offers further support for physiologically relevant ephaptic interactions in the retina.
Highlights
Feedback mechanisms in neural systems provide pathways for reciprocal actions of pre- and post-synaptic cells
Effect of pH buffering on feedback responses in cones and horizontal cells Several studies have shown that HEPES, a rapidly acting pH
Because Davenport et [14] measured surround responses of ganglion cells and roll-back responses in horizontal cells, which are indirect measures of cone feedback, we repeated their experiments on goldfish retina in order to compare the effect of HEPES on feedback responses measured directly in cones and indirectly in horizontal cells
Summary
Feedback mechanisms in neural systems provide pathways for reciprocal actions of pre- and post-synaptic cells. According to the hemichannel hypothesis, surround illumination causes the horizontal cell to hyperpolarize, leading to an increase in the current flowing through both the hemichannels and the glutamategated channels [7,9]. This current flow produces a voltage drop along the high resistance path of the synaptic cleft, thereby shifting the Ca2+-current in the cones to more negative potentials and enhances glutamate release from the cone terminal. An alternative account suggests that horizontal cell hyperpolarization increases the Ca2+-current to promote transmitter release through a hemichannel-mediated ephaptic mechanism
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