By monitoring calcium signals in vivo, we find that an olfactory stimulus reduces the gain with which changes in luminance or temporal contrast are transmitted through the OFF pathway, while also increasing sensitivity at lower light levels (Figures 1, 2, and 3). The results demonstrate that the calcium signal controlling neurotransmission from bipolar cells is

a key site for regulating the flow of the visual information. The observed modulation of presynaptic BMS-754807 manufacturer calcium responses is likely to contribute to the increase in luminance sensitivity observed behaviorally when the ORC circuit is activated (Maaswinkel and Li, 2003 and Huang et al., 2005). The chemical signal coordinating these changes in retinal performance has been suggested to be a reduction in dopamine release. Strong evidence for this idea is provided by the demonstration that a blocker of dopamine release and reuptake suppresses the change in synaptic gain and sensitivity normally caused by an olfactory stimulus (Figure 6). Manipulations of dopamine receptor activity in vivo are also consistent with this mechanism (Figures 4, 5, and 6) and, in particular, for AZD6244 clinical trial a key role of D1 receptors (Figures 5B and 5D). Finally, we demonstrate

that dopamine regulates the activity of voltage-dependent calcium channels in the synaptic terminals of bipolar cells, providing a direct mechanism for regulating the gain of the visual signal (Figure 7). Of course,

these results do not rule out the possibility that there are other sites at which ORC also regulates the retinal circuit. An overview of changes in the amplitude of the calcium signal through ON and OFF bipolar cell terminals Bay 11-7085 is shown in Figure 8. The response is quantified as the relative change in SyGCaMP2 fluorescence caused by a bright step of light applied from darkness, and the various experimental conditions are ordered according to the expected level of dopamine activity, with the measurement in 100 nM of the D1 dopamine receptor antagonist SCH 23390 at one extreme and in 200 nM of the agonist ADTN at the other. This comparison reveals a fundamental difference in the sensitivity of the ON and OFF pathways to changes in retinal dopamine levels. Under control conditions, luminance signaling through the OFF pathway is operating at its maximum gain (i.e., similar to that measured in ADTN), whereas signaling through the ON pathway is operating at its minimum gain (measured in SCH 23390). Thus, although an olfactory stimulus that results in decreased dopamine levels may be expected to decrease the gain of signals through the OFF pathway (Figures 1 and 8A), it is not expected to suppress synaptic calcium signals in ON bipolar cells (Figures 1 and 8B). It appears that the ON and OFF pathways have different sensitivities to dopamine.