University of Cambridge > Talks.cam > Adrian Seminars in Neuroscience > Inhibition and adaptationin the outer retina - Intiguing synaptic mechanisms with unexpected molecular players

Inhibition and adaptationin the outer retina - Intiguing synaptic mechanisms with unexpected molecular players

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Kamermans, K. & Fahrenfort I. 2004. Ephaptic interactions within a chemical synapse: hemichannel-mediated ephaptic inhibition in the retina. Current Opinion in Neurobiology 14:1-11.

Vroman, R., Klaassen, L. J., Howlett, M., Cenedese, V., Klooster, J., Sjoerdsma, T., & Kamermans, M. 2014. Extracellular ATP hydrolysis inhibits synaptic transmission by increasing pH buffering in the synaptic cleft. PLOS Biology. Vol. 12, Issue 5. Abstract Neuronal computations strongly depend on inhibitory interactions. One such example occurs at the first retinal synapse, where horizontal cells inhibit photoreceptors. This interaction generates the center/surround organization of bipolar cell receptive fields and is crucial for contrast enhancement. Despite its essential role in vision, the underlying synaptic mechanism has puzzled the neuroscience community for decades. Two competing hypotheses are currently considered: an ephaptic and a proton-mediated mechanism. Here we show that horizontal cells feed back to photoreceptors via an unexpected synthesis of the two. The first one is a very fast ephaptic mechanism that has no synaptic delay, making it one of the fastest inhibitory synapses known. The second one is a relatively slow (t ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTP Dase1 hydrolyses extracellular ATP to AMP , phosphate groups, and protons. The phosphate groups and protons form a pH buffer with a pKa of 7.2, which keeps the pH in the synaptic cleft relatively acidic. This inhibits the cone Ca2+ channels and consequently reduces the glutamate release by the cones. When horizontal cells hyperpolarize,the pannexin 1 channels decrease their conductance, the ATP release decreases, and the formation of the pH buffer reduces. The resulting alkalization in the synaptic cleft consequently increases cone glutamate release. Surprisingly, the hydrolysis of ATP instead of ATP itself mediates the synaptic modulation. Our results not only solve longstanding issues regarding horizontal cell to photoreceptor feedback, they also demonstrate a new form of synaptic modulation. Because pannexin 1 channels and ecto-ATPases are strongly expressed in the nervous system and pannexin 1 function is implicated in synaptic plasticity, we anticipate that this novel form of synaptic modulation may be a widespread phenomenon.g in the synaptic cleft. PLOS Biology Vol. 12, Issue 5.

Klaassen, L. J., Sun, Z., Steijaert ,M. N., Bolte, P. Fahrenfort, I., Sjoerdsma, T., Klooster, J., Claassen, Y., Shields, C. R., Ten Eikelder, H. M. M. Janssen-Bienhold, U., Zoidl, G., McMahon, D.G. & Kamermans, M. 2011. Synaptic transmission from horizontal cells to cones is impaired by loss of connexin hemichannels. PlOS Biology Vol.9, Issue 7. Abstract In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a longstanding debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina.

Kamermans, M., Fahrenfort, I., Schultz, K., Janssen-Bienhold, U., Sjoerdsma, T., & Weiler, R. 2001. Hemichannel-Mediated Inhibition in the Outer Retina. Science. Vol 292. 1178.

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