An animal’s ability to survive depends on its sensory systems being able to adapt to a wide range of environmental conditions, by maximizing the information extracted and reducing the noise transmitted. The visual system does this by adapting to luminance and contrast. While luminance adaptation can begin at the retinal photoreceptors, contrast adaptation has been shown to start at later stages in the retina. Photoreceptors adapt to changes in luminance over multiple time scales ranging from tens of milliseconds to minutes, with the adaptive changes arising from processes within the phototransduction cascade. Here we show a new form of adaptation in cones that is independent of the phototransduction process. Rather, it is mediated by voltage-gated ion channels in the cone membrane and acts by changing the frequency response of cones such that their responses speed up as the membrane potential modulation depth increases and slow down as the membrane potential modulation depth decreases. This mechanism is effectively activated by high-contrast stimuli dominated by low frequencies such as natural stimuli. However, the more generally used Gaussian white noise stimuli were not effective since they did not modulate the cone membrane potential to the same extent. This new adaptive process had a time constant of less than a second. A critical component of the underlying mechanism is the hyperpolarization-activated current, I_h, as pharmacologically blocking it prevented the long- and mid- wavelength sensitive cone photoreceptors (L- and M-cones) from adapting. Consistent with this, short- wavelength sensitive cone photoreceptors (S-cones) did not show the adaptive response, and we found they also lacked a prominent I_h. The adaptive filtering mechanism identified here improves the information flow by removing higher-frequency noise during lower signal-to-noise ratio conditions, as occurs when contrast levels are low. Although this new adaptive mechanism can be driven by contrast, it is not a contrast adaptation mechanism in its strictest sense, as will be argued in the Discussion. An animal’s ability to survive depends on its ability to adapt to a wide range of light conditions, by maximizing the information flow through the retina. Here, we show a new form of adaptation in cone photoreceptors that helps them optimize the information they transmit by adjusting their response kinetics to better match the visual conditions. The adaptive mechanism we describe is independent of the cone phototransduction process and is instead mediated by membrane processes in which the hyperpolarization-activated current, I_h, plays a critical role. Consistent with the critical role of this current, we also found that cones sensitive to short wavelengths lacked a prominent I_h current and did not show this new form of adaptation. As voltage-dependent processes underlie the adaptational mechanism, it is only apparent when the stimuli are able to sufficiently modulate the membrane potential of cones. This happens with natural stimuli, which are able to deliver high levels of “effective” contrast. However, even though this new adaptive mechanism can be driven by contrast, we argue in the Discussion that in its strictest sense it is not a contrast adaptation mechanism per se.

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 (τ≈200 ms), highly intriguing mechanism. It depends on ATP release via Pannexin 1 channels located on horizontal cell dendrites invaginating the cone synaptic terminal. The ecto-ATPase NTPDase1 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. At the first retinal synapse, specific cells—horizontal cells (HCs)—inhibit photoreceptors and help to organize the receptive fields of another retinal cell type, bipolar cells. This synaptic interaction is crucial for visual contrast enhancement. Here we show that horizontal cells feed back to photoreceptors via a very fast ephaptic mechanism and a relatively slow mechanism. The slow mechanism requires ATP release via Pannexin 1 (Panx1) channels that are located on HC dendrites near the site where photoreceptors release the neurotransmitter glutamate to HCs and bipolar cells. The released ATP is hydrolyzed to produce AMP, phosphate groups, and protons; these phosphates and protons form a pH buffer, which acidifies the synaptic cleft. This slow acidification inhibits presynaptic calcium channels and consequently reduces the neurotransmitter release of photoreceptors. This demonstrates a new way in which ATP release can be involved in synaptic modulation. Surprisingly, the action of ATP is not purinergic but is mediated via changes in the pH buffer capacity in the synaptic cleft. Given the broad expression of Panx1 channels in the nervous system and the suggestion that Panx1 function underlies stabilization of synaptic plasticity and is needed for learning, we anticipate that this mechanism will be more widespread than just occurring at the first retinal synapse.