Joshua H. Singer

The gain of signaling in primary sensory circuits is matched to the stimulus intensity by the process of adaptation. Retinal neural circuits adapt to visual scene statistics, including the mean (background adaptation) and the temporal variance (contrast adaptation) of the light stimulus. The intrinsic properties of retinal bipolar cells and synapses contribute to background and contrast adaptation, but it is unclear whether both forms of adaptation depend on the same cellular mechanisms. Studies of bipolar cell synapses identified synaptic mechanisms of gain control, but the relevance of these mechanisms to visual processing is uncertain because of the historical focus on fast, phasic transmission rather than the tonic transmission evoked by ambient light. Here, we studied use-dependent regulation of bipolar cell synaptic transmission evoked by small, ongoing modulations of membrane potential (V_M) in the physiological range. We made paired whole-cell recordings from rod bipolar (RB) and AII amacrine cells in a mouse retinal slice preparation. Quasi-white noise voltage commands modulated RB V_M and evoked EPSCs in the AII. We mimicked changes in background luminance or contrast, respectively, by depolarizing the V_M or increasing its variance. A linear systems analysis of synaptic transmission showed that increasing either the mean or the variance of the presynaptic V_M reduced gain. Further electrophysiological and computational analyses demonstrated that adaptation to mean potential resulted from both Ca channel inactivation and vesicle depletion, whereas adaptation to variance resulted from vesicle depletion alone. Thus, background and contrast adaptation apparently depend in part on a common synaptic mechanism.

Primary sensory circuits encode both weak and intense stimuli reliably, requiring that their synapses signal over a wide dynamic range. In the retinal circuitry subserving night vision, processes intrinsic to the rod bipolar (RB) cell presynaptic active zone (AZ) permit the RB synapse to encode signals generated by the absorption of single photons as well as by more intense stimuli. In a study using anin vitroslice preparation of the mouse retina, we provide evidence that the location of Ca channels with low open probability within nanometers of the release sites is a critical determinant of the physiological behavior of the RB synapse. This gives rise to apparent one-to-one coupling between Ca channel opening and vesicle release, allowing presynaptic potential to be encoded linearly over a wide dynamic range. Further, it permits a transition from univesicular to multivesicular release (MVR) when two Ca channels/AZ open at potentials above the threshold for exocytosis. MVR permits small presynaptic voltage changes to elicit postsynaptic responses larger than quantal synaptic noise.

During night (i.e., scotopic) vision in mammals, rod photoreceptor output is conveyed to ganglion cells (GCs), the output cells of the retina, by a specialized neural circuit comprising rod bipolar (RB) and AII amacrine cells. Here, we examined how intrinsic postsynaptic conductances in AIIs contribute to transmission of rod-derived signals. Using paired recordings from synaptically coupled RBs and AIIs, we found that a voltage-gated Na conductance in AII amacrines accelerated EPSPs arising from RB synaptic input. EPSPs also could be amplified by the Na conductance when AIIs were hyperpolarized below resting membrane potential, thereby increasing the availability of Na channels. AII amacrines are coupled electrically, and coupled AII amacrines likely receive common input from individual RBs. Na channel-mediated effects on EPSPs, however, appeared to occur at the single-cell rather than the AII network level. By recording light-evoked synaptic currents from GCs, we determined that the Na channel-dependent acceleration, but not amplification, of RB output by AII amacrines is reflected in the dynamics of AII synaptic output to retinal ganglion cells: synaptic inputs to both ON and OFF GCs are slowed equivalently, although not attenuated in amplitude, when Na channels in AIIs are blocked. Thus, during scotopic vision, Na conductances in AIIs serve to accelerate RB output.

Pronounced multivesicular release (MVR) occurs at the ribbon synapses of sensory neurones that signal via graded potential changes. As MVR increases the likelihood of postsynaptic receptor saturation, it is of interest to consider how sensory synapses overcome this problem and use MVR to encode signals of widely varying intensities. Here, I discuss three postsynaptic mechanisms that permit three different retinal synapses to utilize MVR.

We estimated the size of the readily releasable pool (RRP) of vesicles at a ribbon synapse in the rat retina by making paired voltage-clamp recordings from presynaptic rod bipolar cells (RBCs) and postsynaptic AII amacrine cells in an in vitro retinal slice preparation. The RRP at each active zone was estimated to constitute seven vesicles, in the range of estimated RRP sizes at conventional synapses. During sustained presynaptic Ca²⁺ entry, the RRP could be released with a time constant of about 4 ms. This ribbon synapse exhibited pronounced paired-pulse depression (PPD), which was attributable primarily to vesicle depletion. Recovery from PPD was slow (τ ≈ 4 s) but could be accelerated by increasing the duration of the depressing stimulus. The small RRP and very high release probability likely contribute to the transient characteristics of neurotransmission at RBC synapses.