Mustafa B. A. Djamgoz

Neurobiology and clinical aspects of the outer retina

Development and morphological organization of photoreceptors. Cell biology and metabolic activity of photoreceptor cells: light-evoked and circadian regulation. Determinants of visual pigment spectral location and photoreceptor cell spectral sensitivity. Molecular biology of visual pigment molecules. Phototransduction, excitation and adaptation. Photoreceptor synaptic output: neurotransmitter release and photoreceptor coupling. Photoreceptor-horizontal cell connectivity: synaptic transmission and remodulation. Horizontal cell coupling and its regulation. Cross-talk between cones and in horizontal cells through the feedback circuit in the vertebrate retina. Neurotransmitter release from horizontal cells. The organization of photoreceptor to bipolar synapses in the outer plexiform layer of the vertebrate retina. Photoreceptor-bipolar cell transmission. Functional architecture of mammalian outer retina and bipolar cells. Neurotransmitter release from bipolar cells. Interplexiform cell connectivity in the outer retina. The involvement of Mueller cells in the outer retina. Clinical aspects: outer retinal dystrophies. Clinical aspect: Retinitis pigmentosa. Clinical aspects: Paraneoplastic retinopathy. Clinical aspects: Parkinsons disease.

Nitric oxide induces light-adaptive morphological changes in retinal neurones

THIS study tested the possible involvement of nitric oxide (NO) in light-adaptive morphological changes in the outer retina of a cyprinid fish, the roach. Isolated retinae were treated in the dark by either of two NO-donor compounds (S-nitroso-n-acetylpenicillamine, and sodium nitroprusside), and then studied by light, and electron microscopy; similar results were obtained in both cases. Application of NO induced contraction of cone photo-receptor myoids (i.e. retinomotor movements), and formation of horizontal cell spinules. Accordingly the cone index, and the spinule/ribbon ratio showed 15–20%, and 49–95% change, respectively, compared with controls. These results are consistent with involvement of NO in the light adaptation process in the outer retina of teleost fish.

Nitric oxide inhibits depolarization-induced release of endogenous dopamine in the rabbit retina.

The effect of nitric oxide donor compounds (sodium nitroprusside, hydroxylamine and S-nitroso-N-acetyl-D,L-penicillamine) on depolarization-induced release of endogenous dopamine in the light-adapted, isolated retina of the rabbit was studied by HPLC. All three compounds had the same effect, reducing the amount of dopamine released by up to 90%. The effect was concentration dependent, saturating at 300 microM; it was blocked by the nitric oxide scavenger, mannitol (50 mM), which by itself had no effect on the basal release of dopamine. GABAA receptors were not involved. Possible cellular mechanisms underlying the findings are discussed. It is suggested that the inhibitory interaction between dopamine and nitric oxide could represent a higher order function in the light adaptation process in the retina.

Histochemistry of NADPH-diaphorase-a marker for neuronal nitric oxide synthase-in the carp retina

The nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemical technique was used as a marker to assess the distribution of nitric oxide synthase activity in the carp retina. NADPH-diaphorase activity was found to be present in photoreceptors (rods and cones), horizontal cells, amacrine cells, bipolar cells, Müller cells and ganglion cells. Staining was most prominent in the photoreceptor ellipsoids but was not confined to any particular subtype. The density of the staining within the inner plexiform layer (IPL) was determined by image analysis. There was a broad peak of activity in each sublamina of the IPL, but sublamina b appeared to be relatively more heavily stained. The results taken together suggest that the nitric oxide signalling system could have a broader involvement in retinal function than previously thought. Furthermore, nitric oxide may have a novel mode of action in the retina whereby it could be effective on cells (photoreceptors) that also synthesize it.

Nitric oxide release is induced by dopamine during illumination of the carp retina: serial neurochemical control of light adaptation.

Several lines of indirect evidence have suggested that nitric oxide may play an important role during light adaptation of the vertebrate retina. We aimed to verify directly the effect of light on nitric oxide release in the isolated carp retina and to investigate the relationship between nitric oxide and dopamine, an established neuromodulator of retinal light adaptation. Using a biochemical nitric oxide assay, we found that steady or flicker light stimulation enhanced retinal nitric oxide production from a basal level. The metabotropic glutamate receptor agonist l‐amino‐4‐phosphonobutyric acid, inhibited the light adaptation‐induced nitric oxide production suggesting that the underlying cellular pathway involved centre‐depolarizing bipolar cell activity. Application of exogenous dopamine to retinas in the dark significantly enhanced the basal production of nitric oxide and importantly, inhibition of endogenous dopaminergic activity completely suppressed the light‐evoked nitric oxide release. The effect of dopamine was mediated through the D1 receptor subtype. Imaging of the nitric oxide‐sensitive fluorescent indicator 4,5‐diaminofluorescein di‐acetate in retinal slices revealed that activation of D1 receptors resulted in nitric oxide production from two main spatial sources corresponding to the photoreceptor inner segment region and the inner nuclear layer. The results taken together would suggest that during the progression of retinal light adaptation there is a switch from dopaminergic to nitrergic control, probably to induce further neuromodulatory effects at higher levels of illumination and to enable more efficient spreading of the light adaptive signal.

Photoreceptor-horizontal cell connectivity, synaptic transmission and neuromodulation

Horizontal cells (HCs) are second-order neurons receiving their main synaptic drive from photoreceptors. A minor input may be derived from bipolar cells in the amphibian retina (Lasanky, 1979), whereas in many vertebrates a major modulatory influence is exerted by the interplexiform cells (Chapter 15). HCs occur in a number of morphological forms even in the retina of a given species. They may be axonless or axon-bearing, and the latter may have an axon terminal region which may or may not contact photoreceptors. Thus, in retinas of different species rod and cone photoreceptor inputs can be arranged in a variety of different forms.

Nitric oxide, 2-amino-4-phosphonobutyric acid and light/dark adaptation modulate short-wavelength-sensitive synaptic transmission to retinal horizontal cells.

Light-induced changes in the input resistance (Rin) of external, luminosity (i.e. H1) type horizontal cell (HC) perikarya were studied by the bridge-balance method in light-adapted and dark-adapted retinae of carp. Changes in input resistance (delta Rin) induced by short-(460 nm) and long-wavelength (674 nm) flashes, adjusted in intensity to elicit equal-amplitude membrane voltage responses (equal-voltage condition), were measured. In light-adapted retinae, long-wavelength stimuli increased Rin consistently; in contrast, the increase was much less with short-wavelength stimuli. This equal-voltage chromatic delta Rin difference was lost in dark-adapted retinae whereby the delta Rin (an increase) became the same for short- and long-wavelengths. The chromatic delta Rin difference could be recovered by light adaptation or application of sodium nitroprusside to the dark-adapted retinae. Conversely, the equal-voltage chromatic delta Rin difference was eliminated by injection of NG-monomethyl-L-arginine into H1HCs of the light-adapted retinae or by treating the retinae with 2-amino-4-phosphonobutyrate (APB). These results suggest that H1HCs of the carp retina possess distinct postsynaptic mechanisms which mediate short- and long-wavelength signal transmission. Furthermore, it appears that the short-wavelength-sensitive pathway is active only during the light-adapted state of the retina. Taken together, therefore, the short-wavelength transmission to H1HCs probably operates on an APB-sensitive glutamate receptor, with nitric oxide as a light-adaptive messenger.

Spectral plasticity of H1 horizontal cells in carp retina: Independent modulation by dopamine and light-adaptation

It was shown previously that the spectral sensitivity of luminosity/H1 ‐type horizontal cells (HCs) in carp retinae reflects the absorption spectrum of red‐sensitive cones for long wavelengths but can appear highly variable and‘truncated’in the short‐wavelength region of the spectrum. We have found that light‐adaptation sharpened the red‐sensitive spectral peak and decreased the blue/red response amplitude ratio (B/R ratio), mainly by decreasing the response to short‐wavelength stimuli. The adaptation effect was more pronounced for red background light than for blue. During dark adaptation, the B/R ratio increased steadily. Exogenous dopamine (DA; 5 μM) changed the spectral response profile in a similar way to light‐adaptation. However, the effect of light‐adaptation in reducing the B/R ratio was still seen in retinae bathed in 5 μM DA. This effect of background adaptation was also recorded in retinae bathed in 37 μM haloperidol, as well as in retinae pretreated with 6‐hydroxydopamine (i.e. DA‐depleted). The results suggest that (i) short‐wavelength‐sensitive cones play a dynamic role in determining the spectral response profile of H1 HCs and (ii) spectral response characteristics are modulated independently by exogenous DA and an unknown endogenous neuromodulator which is activated by light‐adaptation.

NADPH diaphorase activity around the suprachiasmatic nucleus in rat brain

Abstract.The ’nicotinamide adenine dinucleotide phosphate diaphorase’ histochemical technique was used as a marker of neuronal nitric oxide synthase to assess the presence of the enzyme in the anterior hypothalamus of the rat. Particular attention was focused on the subparaventricular zone, periventricular area and suprachiasmatic nucleus. The results show that there is strong staining in the anterior hypothalamus particularly in the subparaventricular zone by the perinuclear regions of the suprachiasmatic nucleus, and in the periventricular nucleus. Some diaphorase activity was also seen within the suprachiasmatic nucleus, but this was much weaker than in the surrounding areas. These results, taken together with existing evidence, would further suggest the involvement of nitric oxide in the signal transduction pathway in the suprachiasmatic nucleus.

Spatio-Chromatic Signalling in the Vertebrate Retina

The optical image focussed on the photoreceptor layer of the retina has distributed within it a variety of informative features that represent visual conditions in the surrounding environment. One of these features is colour. In fact, the functional organization of the vertebrate visual system is such that the colour of a given ‘local’ stimulus is not perceived just according to the wavelengths of light reflected from that point but is also influenced by wavelengths emitted from surrounding areas. This spatio-chromatic phenomenon leads to “colour constancy” whereby the colour of an object appears unchanged under different spectral illumination conditions (Land, 1959). Colour constancy has been demonstrated by both psychophysics and electrophysiology in vertebrates as diverse as fish and primates (Zeki, 1980; 1995; Ingle, 1985).