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

on

off

ON

on

off

OFF

on

off

ON/OFF

20 mV

1 s

Figure 14.3 Whole-cell patch-clamp recordings from three different RGCs obtained from the neonatal ferret retina to a flashed spot of light. The onset and offset of the light is denoted above each recording. The cell shown on the top responded only to light onset, the one in the middle responded only to light offset; these neurons had their dendrites stratified in either the ON or OFF sublayer of the IPL respectively. By contrast, the cell whose responses are depicted on the bottom responded to both light onset and offset and the dendrites of this RGC were found to span the ON and OFF sublayers of the IPL.

Treating the developing retina with APB perturbs the stratification of both ONand OFF-RGC dendrites to an approximately equal extent (Bodnarenko and Chalupa, 1993; Bodnarenko et al., 1995; Bisti et al., 1998). It assumes that the effects of APB are basically equivalent in the developing and mature retina. But this is not the case, since both ON and OFF responses can be completely blocked in multistratified RGCs, while only the ON pathway is affected by APB application in the mature retina (Wang et al., 2001). Therefore, we may conclude that the functional circuitry underlying ON–OFF responses in the developing retina is fundamentally different from that found in the mature retina, but the details of these differences remain to be established.

At maturity, the axons of ON-cone and OFF-cone BCs terminate in two distinct strata of the IPL where they synapse onto the dendrites of ON and OFF RGCs. Until recently, nothing was known about the development of BC inputs because it was not feasible to

cellular processes that might be stratified within the IPL prior to the ingrowth of BC axons. A recent study has shown that the axon arbors of cone BCs still form two distinct strata following depletion of all RGCs by cutting the optic nerve on the day of birth (GunhanAgar et al., 2000), suggesting that RGCs are not necessary for the formation of segregated ON and OFF BC inputs. Similar findings have been reported in a zebrafish mutant retina tak/ath5, in which RGCs are never born (Kay et al., 2004).

What about the dendrites of starburst amacrine cells (ACs)? At maturity these processes, which can be identified by cholinergic immunostaining, are organized into two strata within the IPL and are innervated selectively by ONand OFF-cone BCs (Famiglietti et al., 1977; Famiglietti, 1983a,b; Masland et al., 1984; Tauchi and Masland, 1984; Bloomfield and Miller, 1986; Masland and Tauchi, 1986). Moreover, in both the chick (Layer et al., 1997) and the rat (Koulen, 1997), bistratified cholinergic-positive strata are detectable very early in development. In the rat retina, such bands are already present more than a week before the stratified bipolar axon arbors are formed. To assess the role of ACs in establishing proper innervation of the IPL by BCs, cholinergic neurons can be eliminated with a novel immunotoxin using a saporin-anti-VAChT (vesicular acetylcholine transporter) antibody. Virtually all the retinal cholinergic cells were eliminated after a single intraocular injection of this new immunotoxin as early as the day of birth, more than a week before the stratification of BC axons, and despite that, cone BCs were still found to form their segregated projections (Gunhan et al., 2002).

In summary, there are three retinal cell types with processes that are prominently segregated within the IPL of the mature retina: (1) the dendrites of ON and OFF RGCs; (2) the projections of ONand OFF-cone BCs; and (3) the processes of cholinergic ACs. The two segregated bands of cholinergic ACs are the first to appear, but the scaffolding provided by these neurons is not essential for the subsequent stratification of cone BCs (Gunhan et al., 2002). Moreover, the stratification of cholinergic processes and cone bipolar projections appears to occur without any obvious refinement, while the dendritic processes of RGCs undergo major structural reorganization to achieve their mature stratified state. Thus, while glutamate release by BCs regulates the stratification of RGC dendrites, the normal ingrowth of cone BCs does not require the presence of RGCs (Gunhan-Agar et al., 2000). In some species such as the cat, the stratification of RGC dendrites commences prior to birth (Bodnarenko et al., 1995), which implies that glutamate release occurs independent of visual input.

Complex receptive fields – insights from a reptilian model

In the last decade, the turtle retina has proven to be an interesting model for studying receptive field development. The reason is that in turtle, as opposed to mammals, embryonic RGCs already have robust light responses. They can be driven by light from embryonic stage 23 (S23) (about three weeks prior to hatching), almost coinciding with the onset of spontaneous bursting activity in these cells (S22) (Sernagor and Grzywacz, 1995). However, at that time, their light responses are immature. Receptive fields are initially small,

continuing to expand until about a month post-hatching, when they reach their mature sizes. Surprisingly, RGCs at the early stages respond well to several directions of movement or orientation of the stimulus light edge. This is in contrast to maturity when these cells show a clear preference for a single direction of motion or orientation, or have no preference at all (Sernagor and Grzywacz, 1995). The proportion of RGCs that have circular receptive fields also increases with maturation.

Theoretical studies have suggested that the response to multiple directions or orientations of motion of immature turtle RGC receptive fields is due to polarized and poorly branched dendritic arbors (Burgi and Grzywacz, 1997, 1998). However, concomitant intracellular labelling of embryonic RGCs with Lucifer yellow and mapping of their responses to moving light edges only occasionally reveals a good match between structure and function (Mehta and Sernagor, 2006a). Moreover, large-field RGCs reach peak dendritic proliferation by S25 (following which they undergo pruning), one week prior to hatching (Mehta and Sernagor, 2006b), when their receptive fields still show a high incidence of embryonic irregularities, or ‘anisotropies’ (Sernagor and Grzywacz, 1995). Thus, rather than being predicted by the shape of dendritic arbors, the responses to multiple directions of movement may arise from immature, sparse sets of excitatory and inhibitory synaptic inputs.

Early neural activity and developing retinal receptive fields

It has generally been assumed that the retina is mature by the time of eye opening (Daw, 1995) and, therefore, few studies have focused on the involvement of visual experience in the maturation of retinal function. For example, one of the earliest studies on that subject showed that visual experience does not affect the development of receptive fields of RGCs in young rabbits (Daw and Wyatt, 1974). Shortly after eye opening, rabbits were reared in an environment with unidirectionally moving stimuli. ON or OFF responses as well as directional selectivity developed normally. It is, however, difficult to interpret these results, because rabbit RGC receptive fields are fairly mature by the time of eye opening (Masland, 1977) and it is very likely that it is too late at that stage for visual experience to have an impact on developing connections. However, even at that time, these observations could not rule out that electrical activity per se may guide developing retinal receptive fields.

More recent studies demonstrate a regulatory role for visual experience in the development of mammalian RGC responses to light. Indeed, dark rearing from early postnatal life transiently suppresses the developmental increase in peak amplitude and time-to-peak light-driven responses normally observed in mouse RGCs after eye opening (Tian and Copenhagen, 2001). Electroretinograms from these animals reveal that visual deprivation reversibly enhances synaptic function in the outer retina and weakens it in the inner retina, suggesting that synaptic development and plasticity does continue after eye opening in the mammalian retina.

In turtle, where RGCs become sensitive to light much earlier (see Complex receptive fields – insights from a reptilian model, p. 297), experimental manipulations that modify spontaneous activity in vivo affect the development of RGC receptive field properties.

Dark rearing from hatching prolongs the period of spontaneous activity and retinal waves (Sernagor et al., 2003) and results in larger receptive fields (Sernagor and Grzywacz, 1996). On the other hand, when cholinergic transmission is chronically blocked from embryonic stages by in vivo application of curare, receptive field areas remain small (Sernagor et al., 2001). Moreover, exposure to curare from the day of hatching prevents the dark-induced expansion of receptive fields (Sernagor and Grzywacz, 1996). These observations suggest that it is the mere presence of spontaneous activity rather than visual experience that really matters for the expansion of receptive field areas. Both curare treatment and dark rearing reduce the amount of mature RGCs with circular receptive fields, while the incidence of circular receptive fields in dark-reared turtles was similar to that of either darkor lightreared turtles whose retinas had been exposed to curare from hatching (Sernagor et al., 2001). Finally, when waves are chronically made larger and stronger (by increasing the wave cellular recruitment and spatial extent) by enhancing cholinergic activity through the blockade of anticholinesterase with neostigmine from S21 or by blocking γ-aminobutyric acid A receptors with bicuculline from S24, the degree of receptive field anisotropies is also lower (Mehta and Sernagor, unpublished results). Taken together, these observations indicate that retinal waves may be important in guiding the maturation of RGC receptive fields.

The role of retinal waves in the stratification of retinal RGC dendrites has also been examined (Bansal et al., 2000). Recall, as discussed in Chapter 13, that β2−/− mice exhibit no correlated activity, although individual RGCs do manifest spikes. In these animals stratified dendrites are formed, but this developmental process is delayed compared with that in wildtype mice. This indicates that retinal waves are not essential for the formation of ON and OFF stratified retinal pathways.

As discussed above, Tian and Copenhagen (2003) demonstrated that visual experience is required for the maturation of ON and OFF responses in mouse RGCs, showing that light is important for the maturation of retinal function in mammals. In that study, dark rearing prevents the normal developmental loss of RGCs responding to both ON and OFF light stimuli. Concomitantly, light deprivation prevents the normal course of age-related loss of bistratified RGCs (see Section 14.3.2).

These observations in mouse suggest that manipulating early neural activity can alter the organization of dendritic arbors of RGCs. Modifying early activity changes dendritic organization in turtle RGCs as well. Dark rearing leads to abnormally high dendritic proliferation (there is an increase both in branch number and length), whereas curare treatment leads just to the opposite (Sernagor et al., 2001; Sernagor and Mehta, 2001; Mehta and Sernagor, 2006b). These structural changes may explain, in part, the enhancement and reduction in receptive field size in dark-reared and curare-treated animals, respectively.

14.4 Concluding remarks

This chapter has reviewed the earliest light responses that can be detected in the developing vertebrate retina.

It is now established that ipRGCs are present and functional from the day of birth in mammals, long before vision is possible through the image-forming pathway. This significant discovery is undoubtedly going to change our perception of how important early visual experience is for the maturation of the visual system and circadian rhythmicity.

The chapter has also reviewed the early light responses in the image-forming pathway, from photoreceptors to RGCs, with an emphasis on the development of ON–OFF responses and RGC complex receptive field properties.

Collectively, the available evidence on the development of retinal ON and OFF pathways would seem to suggest that retinal interneurons follow a set of developmental rules distinct from those obeyed by RGCs (cf. Chalupa and Gunhan, 2004). The morphological properties of dendrites (as well as axon terminals) of RGCs undergo considerable reshaping during the course of normal development and they appear to be susceptible to various types of environmental manipulation. By comparison, the processes of cholinergic ACs and cone BCs appear more rigidly pre-programmed. It remains to be seen whether this generalization gains support as we continue to accumulate new information on the development of retinal circuitry.

Studies on the role of early activity in guiding the development of light responses suggest that the maturation of visual function is highly plastic in early postnatal life. Early neural activity, either in the form of spontaneous waves, or in the form of visual experience can influence the development and refinement of retinal circuitry, ultimately influencing how retinal neurons will process visual information once the retina has reached maturity. Moreover, both forms of early activity interact, making the system even more prone to developmental plasticity. In future studies, to reach a better understanding of the specific contribution provided by early activity in shaping retinal function, it will be important to design experiments where distinct aspects of the wave dynamics and visual processing are specifically targeted.

References

Bansal, A., Singer, J. H., Hwang, B. J. et al. (2000). Mice lacking specific nicotinic acetylcholine receptor subunits exhibit dramatically altered spontaneous activity patterns and reveal a limited role for retinal waves in forming on and off circuits in the inner retina. J. Neurosci., 20, 7672–81.

Belenky, M. A., Smeraski, C. A., Provencio, I., Sollars, P. J. and Pickard, G. E. (2003). Melanopsin retinal ganglion cells receive bipolar and amacrine cell synapses. J. Comp. Neurol., 460, 380–93.

Berson, D. M. (2003). Strange vision: ganglion cells as circadian photoreceptors. Trends Neurosci., 26, 314–20.

Berson, D. M., Dunn, F. A. and Takao, M. (2002). Phototransduction by retinal ganglion cells that set the circadian clock. Science, 295, 1065–70.

Bisti, S., Gargini, C. and Chalupa, L. M. (1998). Blockade of glutamate-mediated activity in the developing retina perturbs the functional segregation of ON and OFF pathways. J. Neurosci., 18, 5019–25.

Bloomfield, S. A., Miller, R. F. (1986). A functional organization of ON and OFF pathways in the rabbit retina. J. Neurosci., 6, 1–13.

Bodnarenko, S. R. and Chalupa, L. M. (1993). Stratification of ON and OFF ganglion cell dendrites depends on glutamate-mediated afferent activity in the developing retina. Nature, 364, 144–6.

Bodnarenko, S. R., Jeyarasasingam, G. and Chalupa, L. M. (1995). Development and regulation of dendritic stratification in retinal ganglion cells by glutamate-mediated afferent activity. J. Neurosci., 15, 7037–45.

Bowe-Anders, C., Miller, R. F. and Dacheux, R. F. (1975). Developmental characteristics of receptive organization in the isolated retina eye-cup of the rabbit. Brain Res., 87, 61–5.

Brown, K. T. and Wiesel, T. N. (1961). Localization of origins of electroretinogram components by intra-retinal recording in the intact cat eye. J. Physiol., 158, 257–80.

Burgi, P. Y. and Grzywacz, N. M. (1997). Possible roles of spontaneous waves and dendritic growth for retinal receptive field development. Neural Comput., 9, 533–53.

Burgi, P. Y. and Grzywacz, N. M. (1998). A biophysical model for the developmental time course of retinal orientation selectivity. Vis. Res., 38, 2787–800.

Chalupa, L. M. and Gunhan, E. (2004). Development of On and Off retinal pathways and retinogeniculate projections. Prog. Retin. Eye Res., 23, 31–51.

Dacey, D. M., Liao, H.-S., Peterson, B. et al. (2005). Melanopsin-expressing ganglion cells in primate retina signal color and irradiance and project to the LGN. Nature, 433, 749–54.

Dacheux, R. F. and Miller, R. F. (1981a). An intracellular electrophysiological study of the ontogeny of functional synapses in the rabbit retina. I. Receptors, horizontal, and bipolar cells. J. Comp. Neurol., 198, 307–26.

Dacheux, R. F. and Miller, R. F. (1981b). An intracellular electrophysiological study of the ontogeny of functional synapses in the rabbit retina. II. Amacrine cells. J. Comp. Neurol., 198, 327–34.

Dann, J. F., Buhl, E. H. and Peichl, L. (1988). Postnatal dendritic maturation of alpha and beta ganglion cells in cat retina. J. Neurosci., 8, 1485–99.

Daw, N. W. (1995). Visual Development. New York: Plenum Press.

Daw, N. W. and Wyatt, H. J. (1974). Raising rabbits in a moving visual environment: an attempt to modify directional sensitivity in the retina. J. Physiol., 240, 309–30.

Dick, O., Dieck, S. T., Altrock, W. D. et al. (2003). The pre-synaptic active zone protein Bassoon is essential for photoreceptor ribbon synapse formation in the retina. Neuron, 37, 775–86.

Dowling, J. E. (1987). The Retina; an Approachable Part of the Brain. Cambridge, MA: Harvard University Press.

Dubin, M. W., Stark, L. A. and Archer, S. M. (1986). A role for action-potential activity in the development of neuronal connections in the kitten retinogeniculate pathway. J. Neurosci., 6, 1021–36.

Euler, T. and W¨assle, H. (1995). Immunocytochemical identification of cone bipolar cells in the rat retina. J. Comp. Neurol., 361, 461–78.

Fahrenkrug, J., Nielsen, H. S. and Hannibal, J. (2004). Expression of melanopsin during development of the rat retina. NeuroReport, 15, 781–4.

Famiglietti, E. V. Jr. (1983a). ‘Starburst’ amacrine cells and cholinergic neurons: mirror-symmetric on and off amacrine cells of rabbit retina. Brain Res., 261, 138–44.

Famiglietti, E. V. Jr. (1983b). On and off pathways through amacrine cells in mammalian retina: the synaptic connections of ‘starburst’ amacrine cells. Vis. Res., 23, 1265–79.

Famiglietti, E. V. Jr. and Kolb, H. (1976). Structural basis for ON-and OFF-center responses in retinal ganglion cells. Science, 194, 193–5.

Famiglietti, E. V. Jr, Kaneko, A. and Tachibana, M. (1977). Neuronal architecture of on and off pathways to ganglion cells in carp retina. Science, 198, 1267–9.

Gunhan, E., Choudary, P. V., Landerholm, T. E. and Chalupa, L. M. (2002). Depletion of cholinergic amacrine cells by a novel immunotoxin does not perturb the formation of segregated on and off cone bipolar cell projections. J. Neurosci., 22, 2265–73.

Gunhan-Agar, E., Kahn, D. and Chalupa, L. M. (2000). Segregation of on and off bipolar cell axonal arbors in the absence of retinal ganglion cells. J. Neurosci., 20, 306–14.

Hahm, J. O., Langdon, R. B. and Sur, M. (1991). Disruption of retinogeniculate afferent segregation by antagonists to NMDA receptors. Nature, 351, 568–70.

Hannibal, J. and Fahrenkrug, J. (2004). Melanopsin containing retinal ganglion cells are light responsive from birth. NeuroReport, 15, 2317–20.

Hattar, S., Liao, H. W., Takao, M., Berson, D. M. and Yau, K. W. (2002). Melanopsincontaining retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science, 295, 1065–70.

Kay, J. N., Roeser, T., Mumm, J. S. et al. (2004). Transient requirement for ganglion cells during assembly of retinal synaptic layers. Development, 131, 1331–42.

Koulen, P. (1997). Vesicular acetylcholine transporter (VAChT): a cellular marker in rat retinal development. NeuroReport, 8, 2845–8.

Layer, P. G., Berger, J. and Kinkl, N. (1997). Cholinesterases precede “ON-OFF” channel dichotomy in the embryonic chick retina before onset of synaptogenesis. Cell Tissue Res., 288, 407–16.

Leard, L. E., Macdonald, E. S., Heller, H. C. and Kilduff, T. S. (1994). Ontogeny of photic-induced c-fos mRNA expression in rat suprachiasmatic nuclei. NeuroReport, 5, 2683–7.

Libby, R. T., Lavallee, C. R., Balkema, G. W., Brunken, W. J. and Hunter, D. D. (1999). Disruption of laminin β2 chain production causes alterations in morphology and function in the CNS. J. Neurosci., 19, 9399–411.

Masland, R. H. (1977). Maturation of function in the developing rabbit retina. J. Comp. Neurol., 175, 275–86.

Masland, R. H. and Tauchi, M. (1986). The cholinergic amacrine cells. Trends Neurosci., 9, 218–23.

Masland, R. H., Mills, J. W. and Hayden, S. A. (1984). Acetylcholine-synthesising amacrine cells: identification and selective staining by using radioautography and fluorescent markers. Proc. R. Soc. London B. Biol. Sci., 223, 79–100.

Maslim, J. and Stone, J. (1988). Time course of stratification of the dendritic fields of ganglion cells in the retina of the cat. Brain Res. Dev. Brain Res., 44, 87–93.

Mehta, V. and Sernagor, E. (2006a). Receptive-field structure function correlates in developing turtle retinal ganglion cells. Eur. J. Neurosci., In press.

Mehta, V. and Sernagor, E. (2006b). Early neural activity and dendritic growth in turtle retinal ganglion cells. Eur. J. Neurosci., In press.

Milam, A. H., Dacey, D. M. and Dizhoor, A. M. (1993). Recoverin immunoreactivity in mammalian cone bipolar cells. Vis. Neurosci., 10, 1–12.

Miller, E. D., Tran, M. I., Wong, G. K., Oakley, D. M. and Wong, R. O. (1999). Morphological differentiation of bipolar cells in the ferret retina. Vis. Neurosci., 16, 1133–44.

Munoz Llamosas, M., Huerta, J. J., Cernuda-Cernuda, R. and Garcia-Fernandez, J. M. (2000). Ontogeny of a photic response in the retina and suprachiasmatic nucleus in the mouse. Brain Res. Dev. Brain Res., 120, 1–6.

Nelson, R. and Kolb, B. (2004). ON and OFF pathways in the vertebrate retina and visual system. In The Visual Neurosciences, ed. L. M. Chalupa and J. S. Werner. Cambridge, MA: MIT Press, pp. 260–78.

Nelson, R., Famiglietti, E. V. Jr and Kolb, H. (1978). Intracellular staining reveals different levels of stratification for onand off-center ganglion cells in cat retina. J. Neurophysiol., 41, 472–83.

Pearlman, A. L. and Sheppard, A. M. (1996). Extracellular matrix in early cortical development. Prog. Brain Res., 108, 117–34.

Provencio, I., Jiang, G., De Grip, W. J., Hayes, W. P. and Rollag, M. D. (1998). Melanopsin: an opsin in melanophores, brain, and eye. Proc. Natl. Acad. Sci. U. S. A., 95, 340–5.

Ramoa, A. S., Campbell, G. and Shatz, C. J. (1988). Dendritic growth and re-modeling of cat retinal ganglion cells during fetal and postnatal development. J. Neurosci., 8, 4239–61.

Reppert, S. M. and Schwartz, W. J. (1983). Maternal coordination of the fetal biological clock in utero. Science, 220, 969–71.

Reuter, J. H. (1976). The development of the electroretinogram in normal and light-deprived rabbits. Pflugers¨ Arch., 363, 7–13.

Sekaran, S., Lupi, D., Jones, S. L. et al. (2005). Melanopsin dependent photoreception provides earliest light detection in the mammalian retina. Curr. Biol, 15, 1099–107.

Sernagor, E. (2005). Retinal development: second sight comes first. Curr. Biol., 15, R556–9.

Sernagor, E. and Grzywacz, N. M. (1995). Emergence of complex receptive field properties of ganglion cells in the developing turtle retina. J. Neurophysiol., 73, 1355–64.

Sernagor, E. and Grzywacz, N. M. (1996). Influence of spontaneous activity and visual experience on developing retinal receptive-fields. Curr. Biol., 6, 1503–8.

Sernagor, E. and Mehta, V. (2001). The role of early neural activity in the maturation of turtle retinal function. J. Anat., 199, 375–83.

Sernagor, E., Eglen, S. J. and Wong, R. O. L. (2001). Development of retinal ganglion cell structure and function. Prog. Retin. Eye Res., 20, 139–74.

Sernagor, E., Young, C. and Eglen, S. J. (2003). Developmental modulation of retinal wave dynamics: shedding light on the GABA saga. J. Neurosci., 23, 7621–9.

Tarttelin, E. E., Bellingham, J., Bibb, L. C. et al. (2003). Expression of opsin genes early in ocular development of humans and mice. Exp. Eye Res., 76, 393–6.

Tauchi, M. and Masland, R. H. (1984). The shape and arrangement of the cholinergic neurons in the rabbit retina. Proc. R. Soc. London B. Biol. Sci., 223, 101–19.

Teller, D. Y. (1997). First glances: the vision of infants. The Friedenwald lecture. Invest. Ophthalmol. Vis. Sci., 38, 2183–203.

Thorn, F., Gollender, M. and Erikson, P. (1976). The development of the kitten’s visual optics. Vis. Res., 16, 1145–9.

Tian, N. and Copenhagen, D. R. (2001). Visual deprivation alters development of synaptic function in inner retina after eye-opening. Neuron, 32, 439–49.

Tian, N. and Copenhagen, D. R. (2003). Visual stimulation is required for refinement of On and Off pathways in postnatal retina. Neuron, 39, 85–96.

Tootle, J. S. (1993). Early postnatal development of visual function in ganglion cells of the cat retina. J. Neurophysiol., 69, 1645–60.

Wang, G. Y., Liets, L. C. and Chalupa, L. M. (2001). Unique functional properties of on and off pathways in the developing mammalian retina. J. Neurosci., 21, 4310–7.