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Maarten Kamermans, Rozan Vroman, Lauw Klaassen, Trijntje Sjoerdsma, Robert Smith, Marcus Howlett; The kinetic properties of negative feedback from horizontal cells to cones. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1758.
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© ARVO (1962-2015); The Authors (2016-present)
Horizontal cells (HC) provide negative feedback to cones by modulating the cone Ca-current (Verweij et al, 1996). The two main hypotheses for this feedback pathway are 1) a hemichannel mediated ephaptic feedback mechanism and 2) a proton based feedback mechanism. Evidence for the ephaptic feedback mechanism is based on morphological, pharmacological and genetic experiments (Kamermans et al., 2001; Klaassen et al., 2011). The pH hypothesis is based on the observation that high concentrations of HEPES block negative feedback from HCs to cones (Hirasawa and Kaneko, 2003). The two feedback hypotheses predict different time constants for the modulation of the Ca-current in cones. Due to its electrical nature, the ephaptic feedback hypothesis predicts that the feedback synapse should be very fast and without any delay. On the other hand, since the time constant of the pH change in the synaptic cleft is slow, around 200 ms (Wang & Kramer, ARVO 2012), pH mediated feedback should also be slow. The aim of the present study is to determine the kinetic properties of feedback in order to distinguish between these two proposed mechanisms.
Voltage and current clamp experiments were performed in flat mounted goldfish and zebrafish retinas. Recorded cone currents were transformed to equivalent voltages via the calcium current activation curve.
Negative feedback from HCs modulated the Ca-current of cones. The light onset feedback response in cones could be fitted best with two exponential functions. The short time constant was about 35 ms and the long time constant was about 180 ms. Feedback seemed to be dominated by the fast process (70-80%). The time constant of the light offset response was also very fast; about 30 ms. For comparison, the light on and offset time constant of HCs were both about 30 ms. There was no significant delay between the fast feedback process measured in cones and the HC response. Therefore this might be among the fastest inhibitory synapses known.
Our results show that negative feedback consists of two processes each with a specific time constant. The fast and dominating process is consistent with a hemichannel mediated ephaptic feedback mechanisms whereas the slow process may be due to changes in pH.
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