Dopamine neurones form a discrete plexus with melanopsin cells in normal and degenerating retina
Introduction
A healthy retinal dopamine system underpins fundamental visual functions such as light adaptation, colour vision, contrast sensitivity and visual acuity. Deficits in this system (and associated visual function) are seen in the retina with increasing age and following disease (Djamgoz et al., 1997). In mammals, the production and release of dopamine from specialised amacrine (interplexiform) cells is stimulated by light exposure (Kramer, 1971, Iuvone et al., 1978). Once released, dopamine works both locally at synapses on adjacent neurones and by volume transmission, whereby it affects the functions of a multitude of cells across the retina (Bjelke et al., 1996). Retinal dopamine cells share several physiological characteristics with their counterparts in the brain, including responsiveness to visual stimuli (Dommett et al., 2005).
In the retina, release of dopamine in response to light has previously been considered to be entirely dependent upon photoreceptors in the outer retina (Frucht et al., 1982, Frucht and Melamed, 1984). However, a distinct population of intrinsically photosensitive retinal ganglion cells (ipRGCs) also exist in the inner retina of mammals. These cells signal irradiance information to circadian and non-image forming centres of the brain (Berson et al., 2002, Hattar et al., 2002) and colour information to image forming brain regions in primates (Dacey et al., 2005). The ipRGCs are thought to signal irradiance using melanopsin, a photopigment first described in photosensitive dermal melanophores of the frog (Provencio et al., 1998). In addition to their role in signalling luminance information to the brain, recent evidence strongly implicates ipRGCs in the regulation of local retinal function, specifically that of cone photoreceptors (Barnard et al., 2006).
The aims of the present study were two-fold. Firstly to provide baseline anatomical information concerning interactions between ipRGCs and dopaminergic amacrine cells in health and retinal disease. Secondly to determine the degree to which anatomical connectivity between these two important retinal cell types is conserved between species.
To achieve the first aim we examined the retinae of Royal College of Surgeons (RCS) dystrophic rats and their normal congenic (non-dystrophic) controls. This animal model is a major tool for studying retinal dystrophy and is characterised by a progressive loss of photoreceptors over the first 3 months of life due to defective retinal pigment epithelial (RPE) cells (Dowling and Sidman, 1962, D'Cruz et al., 2000). Despite the loss of classical photoreceptors in these animals, light is still able to modulate the retinal dopamine system (Doyle et al., 2002) and elicit non-image forming functions throughout life (LaVail et al., 1974). In order to achieve the second aim of the study we examined the interaction between ipRGCs and dopaminergic neurones in the human retina.
In order to visualise both retinal cell types together with a synaptic marker on the same section we employed triple immunolabelling techniques. This was achieved using antibodies to melanopsin, tyrosine hydroxylase and numerous components of the presynaptic machinery. In particular, we used vesicular monoamine transporter 2 (VMAT2) to localise sites of dopamine release. This protein packages dopamine into presynaptic vesicles and has been identified at sites of catecholamine production/release in brain (Hoffman et al., 1998) and retina (Witkovsky et al., 2004).
Section snippets
Tissue preparation
Human tissue was obtained from the Eye Bank at Moorfields Eye Hospital, with full local and national (COREC) ethical permission for research use and the protocol of our study adhered to the tenets of the Declaration of Helsinki regarding research involving human tissue. The retinae from two normal human donor eyes aged 38 and 46 years were used in this study.
Rat retinal tissue was obtained from 10 pigmented RCS dystrophic (rdy−/p+) and 10 non-dystrophic (rdy+/p+) control rats (15 weeks of age)
Interaction between melanopsin and dopamine cells in normal and degenerate rat retina
The histological appearance of the RCS rat retina conformed well with previous descriptions of pathology in this animal (Villegas-Perez et al., 1998). There was a full complement of photoreceptors in the outer nuclear layer (ONL) of non-dystrophic rats but an almost complete absence of ONL in dystrophics which was instead replaced by an autofluorescent debris zone (compare Fig. 1A with E). We found melanopsin to be robustly expressed in a population of ganglion cells in the inner retina of both
Discussion
The close spatial proximity between retinal TH and melanopsin-positive processes in rat and human is strongly indicative of direct communication between the two systems, which at the present juncture we conjecture to be unidirectional. The notion of monosynaptic contact between dopaminergic neurones and ipRGCs in mammals is consistent with results from electron microscopy in the mouse retina which show synaptic contact between amacrine cells and ipRGCs (Belenky et al., 2003). However, Belenky
Acknowledgments
The authors would like to thank Dr. Ignacio Provencio for his gift of anti-human melanopsin antibody. This work was supported by grants from the Wellcome Trust awarded to JG, PR and PC.
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