Ординатура / Офтальмология / Английские материалы / Retinal Development_Sernagor, Eglen, Harris, Wong_2006

Wong et al., 1993; Feller et al., 1996). Retinal waves propagate not only within the GCL, but involve ACs as well (Figure 13.4) (Wong et al., 1995; Zheng et al., 2004). Correlated spontaneous activity and propagating waves have been recorded electrophysiologically as well as with Ca2+ imaging in a wide variety of mammals (mouse, rabbit, ferret, cat), chick and turtle (reviewed in Sernagor et al., 2001), and are therefore likely to be a general feature of the developing vertebrate retina. Recently, it has been shown in the rabbit that waves initiated in the inner retina send retrograde signals to differentiating cells in the ventricular zone where slow Ca2+ waves occur in coincidence with the waves in the GCL (Syed et al., 2004a). The exact nature of these signals remains to be elucidated.

Retinal waves have attracted substantial interest since they were discovered more than a decade ago. The reason is that they encode spatiotemporal cues that may provide important information during the wiring of the visual system, when RGC axons establish connectivity with their central targets, or even while intraretinal circuitry is being formed. Bursting patterns appear to be necessary for the strengthening of synaptic transmission (long-term potentiation) between RGCs and their targets in the lateral geniculate nucleus (LGN) (Mooney et al., 1996). Moreover, since neighbouring RGCs project to neighbouring geniculate neurons, temporal correlation between near-neighbours during these retinal waves ensures that neighbouring geniculate cells are coactivated as well. In line with the Hebbian postulate this would result in the refinement of developing retinotopic maps (Crair, 1999; Eglen, 1999; Penn and Shatz, 1999; Wong, 1999). Retinal waves are unlikely to occur simultaneously in both eyes so they have been viewed as inducing coactivation or cooperation between projections originating from the same eye, where a wave will recruit a massive number of RGCs to fire nearly simultaneously, while at the same time causing competition with inputs from the other eye, which is unlikely to manifest such discharges simultaneously. Let us briefly consider the empirical evidence for the role of activity, and retinal waves in particular, in the refinement of retinal projections.

Pharmacological manipulations that eliminate all retinal activity prevent the segregation of eye-specific inputs to the LGN (Shatz and Stryker, 1988; Penn et al., 1998; Huberman et al., 2003), and changing the balance in activity in the two eyes causes an increase in the territory innervated by the more active eye at the expense of the less active eye (Penn et al., 1998; Stellwagen and Shatz, 2002). Such studies demonstrate that retinal activity is required to form segregated eye-specific projections, but they do not address the role of retinal waves per se. In the mammalian retina, waves are mediated in part by cholinergic ACs and nicotinic receptors in the inner retina (see next section), and a number of studies have now exploited this fact to examine the effects of manipulating wave activity on the formation of segregated retinal-LGN inputs as well as retinotopic organization. In mice lacking the β2 subunit of the nicotinic receptor (β2−/−) retinal waves are not present, although individual RGCs fire spikes at seemingly normal discharge rates (Bansal et al., 2000). Thus, the β2−/− mice have provided an opportunity to assess the role of retinal waves in the development of the retina and retinal projections. These mutants have been found to exhibit a number of abnormalities in the organization of their visual system, including a failure to form normally segregated retinogeniculate projections (Rossi et al., 2001; Muir-Robinson

et al., 2002, Torborg et al., 2004) as well as a lack of refined retinotopy in the LGN and the superior colliculus (Grubb et al., 2003; McLaughlin et al., 2003), and unexpectedly, an abnormal spatial segregation of ONand OFF-centre LGN cells (Grubb et al., 2003). These studies on β2−/− mice would seem to lend support to the notion that retinal waves are essential for the normal segregation of retinogeniculate projections, as well as a number of other salient properties of the visual system. By contrast, in newborn ferrets in which correlated retinal activity has been disrupted by intraocular injections of an immunotoxin that targets cholinergic ACs, segregated retinogeniculate projections are formed normally (Huberman et al., 2003). Complete blockade of retinal activity by pharmacological treatment of the newborn ferret retina prevents segregation of ocular projections, in line with what has been reported by other studies cited above. Thus, unlike the studies on β2−/− mice, the work on the immunotoxin-treated ferrets indicates that retinal activity plays a permissive rather than an instructive role in the formation of segregated ocular inputs. A possible means to reconcile these findings on the mutant mouse and immunotoxin-treated ferret has been cogently discussed recently by Grubb and Thompson (2004, and see also Torborg et al., 2004). Collectively, these studies underscore the fact that further work is required to identify the mechanisms responsible for the formation of segregated left and right eye inputs and to establish the role of retinal waves in the formation of the visual system.

13.3.3Cellular mechanisms underlying the generation and propagation

of retinal waves

A number of studies have been concerned with the important issues of how rhythmic bursting is generated in RGCs and what mechanisms lead to the propagation of activity across the retina.

Both acetylcholine and glutamate play an important role in the generation of retinal waves, but their relative contributions are age-dependent. At early stages, nicotinic cholinergic neurotransmission is necessary to generate correlated spontaneous bursting activity in RGCs (Sernagor and Grzywacz, 1996, 1999) and to propagate the waves (Feller et al., 1996; Catsicas et al., 1998; Wong et al., 1998; Bansal et al., 2000; Sernagor et al., 2000; Wong and Wong, 2000; Zhou and Zhao, 2000; Sernagor et al., 2003; Syed et al., 2004b). The cholinergic inputs originate from starburst ACs, the only cholinergic neurons in the retina (Masland and Tauchi, 1986; Vaney, 1990). Indeed, simultaneous patch-clamp recordings from a RGC and a presumed cholinergic AC have demonstrated that these two cell types, are coactivated during spontaneous bursting activity (Zhou, 1998) (Figure 13.4). Using computer-modelling approaches, Feller et al. (1997) suggested that uncorrelated spontaneous activity in the ACs spreads laterally to other ACs and converges onto neighbouring RGCs to produce correlated waves. However, this cannot be the sole mechanism for initiating and propagating retinal waves because these ACs also receive synaptic input (Zhou, 1998; Zheng et al., 2004), and because other neurotransmitters, secreted by ACs or by other cell types, regulate the spatiotemporal properties of the waves. In the presence of elevated

adenosine, waves become more frequent and they increase in size (Stellwagen et al., 1999). On the other hand GABAergic neurotransmission does not affect the wave spatiotemporal properties at early stages (Stellwagen et al., 1999; Sernagor et al., 2003).

At later stages, wave control switches from acetylcholine to glutamate (Wong et al., 1998; Sernagor et al., 2000; Bansal et al., 2000; Wong and Wong, 2000; Zhou and Zhao, 2000; Syed et al., 2004b). However, both neurotransmitters are required at all times in turtle retina (Sernagor and Grzywacz, 1999; Sernagor et al., 2003). It has been suggested that acetylcholine mediates lateral propagation while glutamate may be involved in local excitability but does not regulate propagation per se (Sernagor and Grzywacz, 1999), so that acetylcholine influences the wave extent, whereas glutamate modulates their speed (Sernagor et al., 2000, 2003). In turtle and ferret, the contribution of glutamate is largely mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate rather than by N-methyl-D-aspartate (NMDA) receptors (Sernagor and Grzywacz, 1999; Wong et al., 2000; Sernagor et al., 2003), while in chick it appears to be mediated equally by both subtypes (Wong et al., 1998; Sernagor et al., 2000). Glutamate is presumably secreted by BCs but other sources such as RGC collaterals or direct projections from immature rods and cones are possible (see Section 13.2). Other neurotransmitters switch function with development. Nicotinic cholinergic neurotransmission switches to muscarinic in neonatal rabbit (Zhou and Zhao, 2000; Syed et al., 2004b). γ-Aminobutyric acid and glycine, which also participate in wave modulation at later stages (see below), shift from being functionally excitatory to inhibitory (GABA – ferret: Fischer et al., 1998; turtle: Sernagor et al., 2003; rabbit: Zheng et al., 2004; glycine – rabbit: Zhou, 2001).

13.3.4 Gap junctions: do they mediate wave propagation?

Gap junctions represent an attractive mechanism for mediating wave propagation, and we have already seen that they are involved in vertical (Catsicas et al., 1998) and horizontal propagations through the ventricular zone before synaptogenesis (Syed et al., 2004a). Once synaptic contacts have been established in the chick IPL, pharmacological blockade of gap junctions suppresses spontaneous activity (Wong et al., 1998), suggesting some contribution to the wave generation process. Nevertheless, there is no unequivocal demonstration that gap junctions are necessary for wave propagation. Indeed, although tracer-coupling studies in the developing ferret retina indicate that α and γ RGCs demonstrate homologous coupling (Penn et al., 1994), there is no coupling between β cells despite their participation in the waves (Wong et al., 1993; Wong and Oakley, 1996). Moreover, gap junction blockade in turtle does not alter wave properties (Sernagor, unpublished observations).

13.3.5 Age-related changes in wave dynamics

Correlated spontaneous bursting activity and waves occur only during a finite temporal period of development. If such spontaneous activity were to persist once the retina becomes

capable of being driven by light, it would interfere with visual responses. It is therefore important to understand what triggers the disappearance of retinal waves.

Both spatial and temporal aspects of wave propagation change with development. At early stages, waves spread relatively fast (at a speed of several micrometres per second) over large retinal areas (reviewed in Sernagor et al., 2001). In a longitudinal study of the changes in retinal wave dynamics in turtle, spanning the last three gestational weeks (gestation takes eight weeks) until a month post-hatching, waves dramatically slow down at embryonic Stage 25 (S25), a week before hatching. Towards hatching they become patches within which RGCs fire in near synchrony, occurring at random both in time and in location (Sernagor et al., 2003; see also Sernagor et al., 2001, Sernagor and Mehta, 2001) (Figure 13.2). These patches become smaller and eventually disappear about one month post-hatching. This gradual restriction in lateral propagation is due to developmental changes in the expression of GABAA responses (Sernagor et al., 2003). Activity of GABAA receptors is not involved in the early synaptic network that generates fast and wide-spreading waves. However, at S25, when the waves suddenly slow down and become narrower, they are modulated by GABA acting through type-A receptors. The GABAA responses at that time are excitatory, as has been reported in many parts of the immature CNS (Ben-Ari, 2002), becoming gradually inhibitory, until there is no correlated spontaneous activity, about one month later. When glutamic acid decarboxylase, the enzyme that synthesizes GABA, is blocked at post-hatching stages with a drug called allylglycine, leading to a decrease in endogenous GABA, spontaneous activity is stronger than in agematched controls, and it even exhibits propagation (Figure 13.3a), presumably because the synaptic network generating spontaneous activity is relieved from GABAergic inhibition (Figure 13.4). These developmental changes in the dynamics of spontaneous activity coincide with the upregulation in the IPL of the K+–Cl− membrane cotransporter KCC2 that extrudes Cl− from mature cells (Figure 13.3b), thereby causing the equilibrium potential for Cl− to shift to more hyperpolarized levels, so that GABAA responses become inhibitory.

Several studies suggest that GABA is important in controlling the disappearance of retinal waves in mammals as well. An elegant recent study, employing dual patch-clamp recordings and Ca2+ imaging from pairs of rabbit starburst ACs, shows that these cells make reciprocal GABAergic synapses with each other, and that the GABAergic responses switch from excitatory to inhibitory while the waves disappear (Zheng et al., 2004; see also Zhou, 2001; Syed et al., 2004b) (Figure 13.4). Moreover, GABA shifts from excitatory to inhibitory around P15 to P18 in ferret (Fischer et al., 1998), shortly before waves stop propagating (Wong et al., 1993). In addition, vesicular GABAergic neurotransmission occurs at early stages (P1 to P5) at conventional synapses in the rodent inner retina (Johnson et al., 2003; see Section 13.2), while it has a depolarizing effect on RGCs in mouse (Bahring et al., 1994) and in all cell types in the rabbit (Huang and Redburn, 1996). Imaging of intracellular Cl− in developing RGCs of the Enhanced Yellow Fluorescent Protein mouse shows that there is a marked increase in the driving force for Cl− from P1 to P9 (when waves are known to occur) to P30 to P36 (when waves have disappeared) (Sernagor, Mutoh and Kn¨opfel,

(a)

(b)

Figure 13.3 The role of GABA in the generation of retinal waves. (a) Time-lapse images (taken every 0.4 s) of spontaneous activity in the turtle retina at seven days post-hatching (PH7). The activity was recorded optically, with RGCs loaded with the Ca2+ -sensitive dye, Ca2+ green dextran. The background fluorescence is subtracted from the image, so that only increases in fluorescence, associated with neural activity, are seen. In control conditions (left panels), the activity is weak and patchy at that age. Following two days incubation in allylglycine, a drug that blocks the synthesis of GABA, therefore reducing the endogenous GABA levels in the tissue, the activity is much stronger, and even propagates (right panels), indicating that GABA has an inhibitory effect on spontaneous activity at post-hatching stages. (b) Immunofluorescence of KCC2, the transporter that extrudes Cl− from mature cells in the turtle retina. Cell nuclei are labelled with 4, 6-diamidino-2-phenylindole (DAPI). KCC2 expression is limited to the plexiform layers. At S25, KCC2 expression is relatively weak (this is when GABA is excitatory). At PH21 days, KCC2 levels have increased significantly in the IPL, and there are two sub-bands of stronger expression (white asterisks), presumably corresponding to the

EARLY AMACRINE–GANGLION CELL NETWORK – WAVES

MATURE AMACRINE–GANGLION CELL NETWORK – NO WAVES

nAChR GABAAR-inhibition

Ganglion cells

Figure 13.4 Amacrine–ganglion cell interactions during the period of spontaneous waves (upperpanel) and in maturity (lower panel). The diagram is based on findings from rabbit (Zheng et al., 2004) and turtle (Sernagor et al., 2003). During the period of spontaneous waves, ACs make direct connections among themselves as well as with RGCs. These connections are all excitatory: cholinergic nicotinic (nACh) and GABAergic (GABAA). The GABAergic connections are excitatory because of high intracellular Cl− . These connections enable lateral propagation within the amacrine network as well as across the GCL, resulting in propagating waves. Later on, the cholinergic nicotinic connections between ACs withdraw (they remain between ACs and RGCs) and GABAA responses become inhibitory, resulting in the disappearance of correlated spontaneous activity.

←

Figure 13.3 (cont.) ON and OFF laminas in the IPL. This increase in KCC2 expression suggests that the intracellular concentration of Cl− must be lower at that age, resulting in inhibitory GABAergic responses (and wave disappearance). When GABAergic activity is chronically blocked from S24 to 28 days PH (PH28 BIC), KCC2 expression is weaker in the IPL than in age-matched controls, with a particular emphasis on the inner part of the IPL, where the ON lamina is now lacking stronger KCC2 expression. There are still waves in these chronic animals, presumably because of weaker cellular extrusion of Cl− and depolarizing GABAergic responses. GCL, ganglion cell layer; INL, inner nuclear layer; ONL, outer nuclear layer.

unpublished observations), suggesting that GABA-induced Cl− currents are depolarizing during the period of spontaneous waves. Finally, KCC2 expression increases significantly during the second week of postnatal development in rat (Vu et al., 2000).

Apart from changes in the spatial patterns of activity, developmental changes in the temporal firing patterns have been reported in ferret RGCs (Wong and Oakley, 1996). Once eye-specific segregation is complete in the LGN, ON and OFF RGCs develop distinct temporal patterns of spontaneous activity, although both cell types still burst in synchrony. ON cells adopt a much lower burst frequency compared with OFF cells. The emergence of these different ON–OFF rhythms is, once again, related to changes in GABAA neurotransmission. Indeed, GABA becomes inhibitory at the time when ON and OFF rhythms diversify. At that time, GABA suppresses bursting activity in ON RGCs more effectively than in OFF RGCs (Fischer et al., 1998). In addition to differences in GABAergic circuitry, distinct bursting patterns between ON and OFF cells also rely on differences in intrinsic membrane properties between these neurons (Myhr et al., 2001). At still later stages of development, the three major RGC classes in the ferret retina (α, β and γ) gradually attain distinct spontaneous discharge patterns that are superimposed on their collective waves-like discharges (Liets et al., 2003). Presumably, such class-specific discharges also reflect differences in the intrinsic membrane properties of these neurons.

Since GABA has such a strong impact on age-related changes in spontaneous activity patterns, it is important to understand what factors control developmental changes in GABAA activity. Sustained GABAA activity is required for GABA to shift polarity in rodent hippocampal cultures (Ganguly et al., 2001, but see Ludurg et al., 2003). In the turtle retina, chronic blockade of GABAA receptors in vivo during the period of the switch prevents GABAA responses from switching polarity, KCC2 expression remains lower (Figure 13.3b) and as a result, strong spontaneous waves still propagate across the retina at one month posthatching, when normally there is no correlated activity anymore (Leitch et al., 2005).

13.3.6 Why do waves disappear with retinal maturation?

In all species, waves disappear shortly after the onset of visual experience, when RGCs become driven by light. This immediately suggests that exposure to light at birth somehow triggers a mechanism that leads to the disappearance of the waves. In the absence of visual experience, spontaneous bursting activity in turtle RGCs (Sernagor and Grzywacz, 1996) and waves (Sernagor et al., 2003) persist for longer periods post-hatching, suggesting that early visual experience may indeed trigger their disappearance. Interestingly, the activityenhancing effect of visual deprivation acts via GABA. Indeed, GABA does not switch polarity, KCC2 expression is lower and waves keep propagating following one month of rearing in the dark (Sernagor et al., 2003). This intriguing effect remains to be elucidated. Perhaps it works through a direct effect of light on GABAA responses, as has been described in adult rat RGCs (Leszkiewicz and Aizenman, 2003).

The situation is different in mammals, however. In the mouse retina, although dark rearing reversibly suppresses the post-eye-opening surge in spontaneous synaptic events (Tian and Copenhagen, 2001), it does not change the period during which RGCs exhibit correlated activity (Demas et al., 2003). Both in control and in dark-reared animals, correlated spontaneous bursting activity disappears by P21. Hence, the effects of dark rearing upon correlated activity vary from species to species, presumably depending on how much they rely on visual experience during early postnatal life. Mammals depend on maternal protection at birth, whereas newly hatched turtles must immediately rely on visual cues for survival. (For example, marine turtles must run to the sea as soon as they hatch to escape predators and start their long migratory journey.) This suggests that the onset of visual experience may be more vital to reptiles than to mammals. It would be interesting to investigate the effect of dark rearing on other mammalian species relying more on vision than rodents. Interestingly, in adult taurine-deficient cats, RGCs within retinal areas depleted of photoreceptors demonstrate bursting behaviour like immature cells (W. R. Levick, personal communication). This suggests that the emergence of the vertical photoreceptor pathways in the maturing retina merely ‘hides’ the circuitry underlying spontaneous correlated bursting activity and propagating waves.

Whatever the explanation for this discrepancy between species might be, it does not exclude the possibility that a developmental switch in the polarity of GABAA activity is necessary in all species to induce the disappearance of correlated spontaneous activity. Clearly, many more studies manipulating GABAergic systems are required to reach a better understanding of these issues.

13.4 Concluding remarks

This chapter has reviewed the steps leading to the formation of functional synapses in various retinal layers. It has shown that synapse formation proceeds in a centrifugal manner, from the inner to the outer retina, and it occurs first in horizontal connections within the plexiform layers, followed by vertical connections between layers.

The chapter has highlighted the importance of various proteins involved in synaptic release, as well as extracellular matrix components, in guiding the development of the synaptic release machinery. The use of knockout mice has already clarified important issues on the role of many of these proteins (e.g. Bassoon) during the maturation of neurotransmission processes. It is clear that genetic manipulations are still the key experimental approach that will help us, in the near future, to unravel more details on the complex mechanism of synaptogenesis and various associated diseases. Likewise, the development of new knockout mice with different connexin expressions will shed more light on the precise roles of gap junctions during retinal development.

The chapter has also introduced the earliest form of neural activity, which takes the form of synaptically driven spontaneous rhythmic bursting in ACs and RGCs. These bursts

propagate across the retinal surface, enabling synchronization between relatively distant parts of the eye. The possible role played by these waves in guiding the development of retinal projections has been discussed, but it is clear that more work is still required to underpin the precise role of retinal waves in the formation of the visual system. The chapter has also discussed how retinal waves change with development, eventually disappearing in all species during the first postnatal month. Whether visual experience guides wave disappearance is still debatable, and certainly appears to be species-related. There is good evidence that the emergence and maturation of synaptic inhibition is very instrumental in guiding the disappearance of these waves, but more studies manipulating inhibitory systems are still needed to reach a better understanding of these issues.

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