Extrasynaptic release of dopamine and volume transmission in the Retina

In the retina, dopamine is a catecholamine modulator responsible for many of the events that lead to neural adaptation to light (see Witkovsky and Dearry, 1991; Djamgoz and Wagner, 1992). By acting on numerous cell types in the retina, dopamine sets the gain of the retinal networks for vision in the light. Measurements of the amount of dopamine released by the retina showed that there is a basal efflux of dopamine in the dark; the efflux is increased by steady illumination and maximal with flickering light (see Witkovsky and Dearry, 1991; Djamgoz and Wagner, 1992). Dopamine acts at multiple levels in the retina: in teleosts, acting at D₂ receptors it induces contraction of cones and movement of melanin granules in pigment epithelial cells (Dearry and Bumside, 1986, 1989). In photoreceptors, acting at D₄ receptors, it inhibits the Na/K ATPase of rods (Shulman and Fox, 1996). Acting at D₂ receptors, it decreases voltage-gated Ca²⁺ current in cones and increases it in rods (Stella and Thoreson, 2000), where, in addition, it inhibits the hyperpolarization-activated current I_h (Akopian and Witkovsky, 1996). Dopamine has complex effects on horizontal and bipolar cells, all mediated by D₁ receptors. It decreases the conductance of the gap junctions between horizontal cells (Piccolino et al., 1984; Lasater and Dowling, 1985; DeVries and Schwartz, 1989), thus reducing the size of their receptive field; in both horizontal and bipolar cells, it potentiates the activity of ionotropic glutamate receptors (Knapp and Dowling, 1987; Maguire and Werblin, 1994), inhibits GABA_c-mediated responses (Dong and Werblin, 1994) and modulates voltage-gated calcium (Pfeiffer-Linn and Lasater, 1998) and potassium (Fan and YazuUa, 1999, 2001) channels. Thus, the overall effect of dopamine in the outer retina is an improvement of contrast detection (Hare and Owen, 1995; see Witkovsky, 2004). In the inner plexiform layer (IPL), dopamine, acting at D₁ receptors. uncouples All amacrine cells (Hampson et al., 1992; Mills and Massey, 1995), potentiates the GABA-induced chloride current of amacrine cells (Feigenspan and Bormann, 1994) and relieves GABA_c inhibition of transmitter release by the synaptic endings of bipolar cells (Wellis and Werblin, 1995). Ultimately, it decreases the sensitivity of ganglion cells and modifies both their spontaneous discharge and the center-surround balance of their receptive fields (Jensen and Daw, 1984, 1986; Jensen 1989, 1991). Retinal dopamine is synthesized by a type of neuron characterized by a large, spherical perikaryon, situated in the vitreal tier of cell bodies of the inner nuclear layer (Fig. 1). Their dendrites form a dense plexus in the scleral stratum (SI) of the inner plexiform layer (IPL); in addition, they give rise to thin, varicose processes, that in the cat and mouse descend into the middle stratum (S3) of the IPL, where they travel long distances before returning to SI (Kolb et al., 1990). In some species, such as the rabbit, the dopaminergic neurons are typical amacrine cells, i.e. their processes do not extend beyond the IPL (Tauchi et al., 1990). In other species, they send additional processes to the outer plexiform layer (OPL), where they form a loose plexus intermeshed with the dendrites of horizontal and bipolar cells. Because of this plexus, whose richness varies greatly in different animal species, the dopaminergic neurons were called interplexiform cells (see Nguyen-Legros, 1988). They are also named type 1 catecholaminergic amacrines, because uptake of catecholamines or antibodies to tyrosine hydroxylase label a second type of retinal neuron, the type 2 catecholaminergic amacrines, that exhibit a smaller perikaryon and possess a dendritic plexus situated in the S3 stratum of the IPL. Very little is known about this second type of catecholaminergic neuron and the nature of its transmitter(s) is unclear. They will not be considered further in this chapter. Thus, dopamine receptors are present throughout the retina, often at a considerable distance from the processes of DA cells (Bjielke et al.,1996; Veruki and Wässle, 1996; Derouiche and Asan, 1999). It was this mismatch between the distribution of the receptors and the localization of the branches of DA cells that prompted the idea that dopamine acts on its targets by volume transmission (Witkovsky et al., 1993). It is generally accepted that dopamine is released upon photopic illumination (see Witkovsky and Dearry, 1991), an indication that DA cells receive input from ON-cone bipolars. Surprisingly, DA cells appeared to be postsynaptic to bipolar endings situated in stratum SI of the IPL (Hokoç and Mariani, 1987; Kolb et al., 1990; Gustincich et al., 1997), which is occupied by axonal arborizations of OFF-cone bipolars. We have recently observed that DA cells also receive a bipolar input on the processes that course in stratum S3 of the IPL (Contini and Raviola, unpublished observations). Since this stratum is occupied by the axonal arborization of ON-bipolar cells, our finding confirms the expectation that DA cells are excited by illumination of the retina. The significance of the bipolar synapses in SI remains to be elucidated. On the other hand, OFF-bipolars have an important role in the excitation of the GABAergic amacrine cell(s) that inhibits the release of dopamine in the dark. Relief of this inhibition contributes to dopamine release upon illumination of the retina. After the discovery of a genetically programmed circadian oscillator in the retina that regulates the synthesis of melatonin (Tosini and Menaker, 1996), DA cells represent an obvious target for the circadian modulator and, indeed, melatonin inhibits release of dopamine in the rabbit (Dubocovich, 1983, 1985; Dubocovich and Hensler, 1986). In Xenopus, this effect is blocked by GABA_A antagonists (Boatright et al., 1994), which led to the suggestion that melatonin receptors reside on GABAergic amacrines. DA cells do receive a substantial input from GABAergic amacrines over the vitreal aspect of the perikaryon and their entire dendritic tree in SI (Kolb et al., 1991; Gustincich et al., 1999), and this input is probably responsible for inhibition of dopamine release in the dark. Melatonin receptors, however, are also present on DA cells (Fujieda et al., 2000). The major output of DA cells is on amacrine cell types which are part of the rod pathway: DA cells establish synapses on All amacrines (Pourcho, 1982; Voigt and Wassle, 1987; Kolb, et al. 1990, 1991; Strettoi et al., 1992), a neuronal type inserted in series along the pathway that carries rod signals to ganglion cells, and S1/S2 amacrine cells (Kolb et al., 1990), that are responsible for an inhibitory feedback onto rod bipolars. The neurotransmitter released at these synapses was not known, but, in addition to dopamine, GABA was a candidate, because both this molecule and its synthetic enzyme glutamic acid decarboxylase are present in the perikarya of DA cells (Kosaka et al., 1987; Wässle and Chun, 1988; Wulle and Wagner 1990). By using triple-label immunocytochemistry and confocal microscopy, we identified a cluster of GABA_A receptors at the postsynaptic active zone of the DA-to-AII amacrine cell synapses (Contini and Raviola, 2003). Since both the GABA vesicular transporter and the vesicular monoamine transporter-2 (VMAT2) are present in the endings of DA cells, we suggested that the synapses between retinal dopaminergic neurons and All amacrine cells are GABAergic and that both GABA and dopamine are released by the presynaptic endings. Finally, a study of global gene expression in single DA cells showed that these neurons secrete insulin, the neuropeptide CART, the cytokine interferon a, and the chemokine monocyte chemoattractant protein-1. They also contain the most common circadian clock-related proteins. Interestingly, cryptochrome 2 is only localized in DA cells and a subset of ganglion cells, supporting the idea that DA cells have a role in the retinal internal clock (Witkovsky et al., 2003; Gustincich et al., 2004). Thus, at the present state of our knowledge, DA cells appear to carry out multiple functions in the retina, each characterized by a different time course. 1) Through their fast, possibly GABAergic synapses on All amacrine cells and S1/S2 amacrine cells, DA cells inhibit the transfer of rod signals to ganglion cells on a time scale in the order of a millisecond. 2) They release dopamine, that acts at a distance by volume transmission on a large number of retinal neurons, presiding over the process of transition from the darkadapted to the light-adapted state. Dopamine also influences gene expression by inducing synthesis of c-fos in amacrine cells (Koistinaho and Sagar, 1995). These functions take place over a time scale of seconds to minutes. 3) DA cells contain the most common circadian clock-related proteins suggesting a role in circadian regulation of retinal function over a time scale of hours. 4) In addition to dopamine, they synthesize four secreted neuroactive molecules whose precise function in the economy of the retina is unknown.