, 1996 and Kubrusly et al., 2008). Intraocular injection of 2 μM vanoxerine had two effects. First, the luminance sensitivity of OFF terminals was increased by a factor of 26 (Figures 6A and 6B) and of ON terminals by a factor of ∼2 (Figures 6D and 6E). Notably, these increases in sensitivity were much smaller than those caused by the dopamine receptor agonist ADTN (Figures 6B and 6E), indicating that increases in dopamine levels were relatively small and not sufficient to saturate dopamine receptors. The second action of vanoxerine was to prevent the application

of methionine from modulating luminance signaling through OFF bipolar cells (Figures 6A and 6C), consistent with the idea that Crizotinib concentration this modulation occurs through changes in dopamine levels. The manipulations EPZ 6438 of dopamine receptors and transporters shown in Figures 4, 5, and 6 support the idea that olfactory stimulation modulates synaptic transmission from OFF bipolar cells by reducing dopamine levels and D1 dopamine receptor activity. What are the cellular mechanisms by which dopamine modulates the visual signal transmitted to the inner retina? In the outer retina of fish and

mammals, dopamine acts through D1 receptors to uncouple horizontal cells providing negative feedback to the synaptic terminals of photoreceptors (Dowling, 1991), but this seems an unlikely mechanism for the selective modulation of transmission through OFF bipolar cells given that these diverge from the ON pathway downstream of photoreceptor output (Schiller et al., 1986). We therefore investigated the possibility that isothipendyl dopamine might also act directly on bipolar cells to modulate synaptic calcium signals. Mixed rod-cone (Mb1) bipolar cells from the retina of goldfish were isolated for electrophysiological recording (Burrone and Lagnado, 1997). In these neurons, voltage-dependent calcium

channels are L-type and localized to the synaptic terminal (Burrone and Lagnado, 1997). In current-clamp configuration, using a standard intracellular solution, addition of 10 μM dopamine depolarized bipolar cells by an average of 30.7 ± 1.5 mV, indicating activation of a net inward current (n = 9; Figures 7A and 7B). The depolarization was completely reversed by blocking voltage-dependent Ca2+ channels with 100 μM cadmium (Catterall et al., 2003), indicating that dopamine potentiates the calcium conductance (n = 6). The Mb1 bipolar cell stands out in a preparation of dissociated retinal neurons because of its large terminal. Of the bipolar cells with small terminals, OFF outnumber ON by 3:1 (Odermatt et al., 2012). We also made recordings from the cell bodies of bipolar cell with small terminals, and in all three cases dopamine caused a depolarization of ∼15 mV. It therefore seems very likely that dopamine also acts to enhance calcium currents in OFF bipolar cells. Heidelberger and Matthews (1994) also observed that dopamine potentiated calcium influx in all morphological types of bipolar cell that they tested.