In vision, balance, and hearing, sensory receptor cells translate sensory stimuli into electrical signals whose amplitude is graded with stimulus intensity. The output synapses of these sensory neurons must provide fast signaling to follow rapidly changing stimuli, while also transmitting graded information covering a wide range of stimulus intensity and sustained for long time periods. To meet these demands, specialized machinery for transmitter release—the synaptic ribbon—has evolved at the synaptic outputs of these neurons. Here we show that acute disruption of synaptic ribbons by photodamage to the ribbon dramatically reduces both sustained and transient components of neurotransmitter release in mouse bipolar cells and salamander cones, without affecting the ultrastructure of the ribbon or its ability to localize synaptic vesicles to the active zone. Our results indicate that ribbons mediate slow as well as fast signaling at sensory synapses, and support an additional role for the synaptic ribbon in priming vesicles for exocytosis at active zones.

Non-spiking cells of several sensory systems respond to stimuli with graded changes in neurotransmitter release and possess specialized synaptic ribbons. Here we show that manipulations to synaptic ribbons caused dramatic effects on mEPSC-like (mlEPSC) amplitude and frequency. Damage to rod-bipolar cell ribbons using fluorophore-assisted light inactivation resulted in the immediate reduction of mlEPSC amplitude and frequency, whereas the first evoked response after damage remained largely intact. The reduction in amplitude could not be recovered by increasing release frequency after ribbon damage. In parallel experiments, we looked at mlEPSCs from cones of hibernating ground squirrels, which exhibit dramatically smaller ribbons than awake animals. Fewer and smaller mlEPSCs were observed postsynaptic to cones from hibernating animals, depolarized cones were able to generate larger mlEPSCs. Our results indicate that ribbon size may influence mlEPSC frequency and support a role for ribbons in coordinating multi-vesicular release.

The visual system can adjust its sensitivity over a wide range of light intensities. Photoreceptors account for some of this adjustment, but there is evidence that postreceptoral processes also exist. To investigate the latter, we pharmacologically mimicked the effects of light stimulation on mouse On bipolar cells, thus avoiding confounding effects of receptoral mechanisms. Here, we report that cGMP selectively enhances responses to dim, but not bright, stimuli through a purely postsynaptic mechanism. This action of cGMP was completely blocked by inhibitors of cGMP-dependent kinase. We propose that cGMP-dependent kinase decreases coupling of the On bipolar cell glutamate receptor to the downstream cascade, thus amplifying small decreases in photoreceptor transmitter levels that would otherwise go undetected by the visual system.

Synaptic transmission from photoreceptors to all types of ON bipolar cells is primarily mediated by the mGluR6 receptor. This receptor, which is apparently expressed uniquely in the nervous system by ON bipolar cells, couples negatively to a nonselective cation channel. This arrangement results in a sign reversal at photoreceptor/ON bipolar cell synapse, which is necessary in order to establish parallel ON and OFF pathways in the retina. The synapse is an important target for 2 nd messenger molecules that are known to modulate synaptic transmission elsewhere in the nervous system, 2 nd messengers that act on a time scale ranging from milliseconds to minutes. This review focuses on two of these molecules, Ca 2+ and cGMP, summarizing our current knowledge of how they modulate gain at the photoreceptor/ON bipolar cell synapse, as well as their proposed sites of action within the mGluR6 cascade. The implications of plasticity at this synapse for retinal function will also be examined.