Morphological properties of mouse retinal ganglion cells.

The mouse retina offers an increasingly valuable model for vision research given the possibilities for genetic manipulation. Here we assess how the structural properties of mouse retinal ganglion cells relate to the stratification pattern of the dendrites of these neurons within the inner plexiform layer. For this purpose, we used 14 morphological measures to classify mouse retinal ganglion cells parametrically into different clusters. Retinal ganglion cells were labeled in one of three ways: Lucifer Yellow injection, 'DiOlistics' or transgenic expression of yellow fluorescent protein. The resulting analysis of 182 cells revealed 10 clusters of monostratified cells, with dendrites confined to either On or Off sublaminae of the inner plexiform layer, and four clusters of bistratified cells, dendrites spanning the On and Off sublaminae. We also sought to establish how these parametrically identified retinal ganglion cell clusters relate to cell types identified previously on the basis of immunocytochemical staining and the expression of yellow fluorescent protein. Cells labeled with an antibody against melanopsin were found to be located within a single cluster, while those labeled with the SMI-32 antibody were in four different clusters. Yellow fluorescent protein expressing cells were distributed within 13 of the 14 clusters identified here, which demonstrates that yellow fluorescent protein expression is a useful method for labeling virtually the entire population of mouse retinal ganglion cells. Collectively, these findings provide a valuable baseline for future studies dealing with the effects of genetic mutations on the morphological development of these neurons.

Glutamate-mediated responses in developing retinal ganglion cells.

Glutamate has been suggested to regulate the development of retinal ganglion cells, but little is known about the functional properties of glutamate receptors during ontogeny of these neurons. Using whole-cell and outside-out patch-clamp recordings, we have characterized the pharmacological, rectification, and kinetic properties of ionotropic glutamate receptors in ganglion cells isolated from fetal and postnatal cat retinas. The fetal cells were studied at embryonic day 33 (E33) to E38, before significant outgrowth of their dendritic processes and prior to the formation of synaptic contacts in the inner plexiform layer. In several respects, the functional properties of early fetal ganglion cells were found to be remarkably similar to those of postnatal cells. In both age groups, glutamate and AMPA produced fast desensitizing currents, kainate yielded large steady-state currents, while applications of NMDA resulted in multiple channel openings. The shapes and amplitudes of these glutamate-gated currents were also similar and the current-voltage relations were nearly linear, with reversal potentials near 0 mV. Moreover, the dose-response curves (to kainate) were virtually identical in the fetal and postnatal neurons. The proportion of neurons responsive to NMDA and non-NMDA agonists was nearly the same in both age groups. This early functional expression of glutamate receptors cannot be involved in the transmission of electrical information in the developing retina because at this stage few ganglion cells are capable of generating action potentials (Skaliora et al., 1993). It is suggested that the early activation of NMDA and non-NMDA receptors in fetal ganglion cells may regulate the outgrowth and stabilization of dendritic processes in these neurons. Our data also revealed some differences in the responses of fetal and postnatal cells to glutamate and its agonists. Thus, the unitary NMDA conductance was found to decrease with age, while the rate of glutamate receptor desensitization increased with age. Also, while virtually all postnatal cells responded to glutamate, the proportion of fetal cells that manifested glutamate-mediated responses was lower. These maturational changes presumably allow retinal ganglion cells to integrate synaptic inputs for the transmission of electrical signals to the visual centers of the brain.

Unique functional properties of on and off pathways in the developing mammalian retina.

In the mature retina, the dendrites of On and Off ganglion cells are segregated into separate sublaminas of the inner plexiform layer, but early in development these processes are multistratified, ramifying more widely within this synaptic layer. The dendritic pattern exhibited by immature ganglion cells suggests that there may be a functional convergence of On and Off pathways in the developing retina, but previous studies have provided evidence against this. Here we demonstrate by patch-clamp recordings and dye filling that ganglion cells with multistratified dendrites respond to the onset, as well as the offset, of light. We further show that, in the dark-adapted retina, the glutamate analog 2-amino-4-phosphonobutric acid abolishes On and Off discharges in ganglion cells with multistratified dendrites. In contrast, in cells with stratified dendrites, this drug selectively blocks On responses. These findings provide evidence for unique functional attributes of On and Off pathways in the developing retina. The properties of immature ganglion cells documented here have important implications for the roles ascribed to neuronal activity in refining connections during the early development of the visual system.

Modeling temporal behavior of postnatal cat retinal ganglion cells.

During development, mammalian retinal ganglion cells (RGCs) go through marked ontogenetic changes with respect to their excitable membrane properties. Voltage-clamp studies conducted in our laboratory have shown that the amplitude, voltage-dependence and kinetics of activation and inactivation (where present) of Na(+), K(+) and Ca(2+) conductances all exhibit developmental changes during a time when the firing patterns of mammalian ganglion cells shift from being transient to being predominantly sustained in nature. In order to better understand the contribution of each conductance to the generation of spikes and spiking patterns, we have developed a model based on our experimental data. For simplicity, we have initially used experimental data obtained from postnatal ganglion cells. At this age the ontogenetic changes observed in the characteristics of the various ionic currents are complete. Utilizing the methods adopted by Hodgkin and Huxley for the giant squid axon, we have determined rate equations for the activation and inactivation properties of the I(A), I(K dr), I(Na), I(Ca L), I(Ca N), and I(leak) currents in postnatal cat RGCs. Combining these with a simplified model of the calcium-activated potassium current (I(KCa)), we have solved and analysed the resulting differential equations. While spikes and spiking patterns resembling experimental data could be obtained from a model in which [Ca(2+)i] was averaged across the whole cell, more accurate simulations were obtained when the diffusion of intracellular Ca(2+) was modeled spatially. The resulting spatial calcium gradients were more effective in gating I(KCa), and our simulations more accurately matched the recorded amplitude and shape of individual spikes as well as the frequency of maintained discharges observed in mammalian postnatal RGCs.

Binocular competition does not regulate retinogeniculate arbor size in fetal monkey.

Binocular interactions play a prominent role in shaping the axonal arbors of geniculocortical fibers and the arbors of Y cells in the retinogeniculate pathway of the fetal cat. Fiber interactions between the two eyes have also been suggested to regulate the formation of retinal projections to the dorsal lateral geniculate nucleus (dlgn) of the fetal monkey, but whether this reflects structural refinements of retinal arbors has not been established. To address this issue, we quantified the morphologic properties of individual fibers in two macaque monkeys at embryonic day (E) 110 and E121 that had an eye removed at E69 and E61, respectively. Fibers were labeled by DiI crystals into the fixed optic tract and were visualized by confocal microscopy. Three measurements were made: the number of branch points within the axon terminal arbor, the total arborization length, and the incidence of axonal side branches on the preterminal axon within the confines of the geniculate. There were no significant differences with respect to these parameters between the prenatal enucleates and normal monkeys of comparable age. This was the case for retinal fibers innervating the magnocellular and the parvocellular segments of the dlgn. The arbors stemming from the remaining eye were widely distributed in the dlgn, with some terminating in territories normally innervated by the other (enucleated) eye. These results lend support to the hypothesis that the expanded projection from the remaining eye to the lateral geniculate nucleus of the prenatally enucleated monkey is due to the maintenance of a contingent of retinal fibers normally eliminated by ganglion cell death.

Retinal mosaics: new insights into an old concept.

It has been known since the middle of the 19th century that different neuronal types are distributed across the retinal surface in non-random arrays: indeed, these arrays, called 'mosaics', have long been considered to be a fundamental feature of retinal organization. However, until recently, little was known about how such mosaics are established during development. In the hope of stimulating further research, this article reviews the current status of three very different approaches to this intriguing general problem. The first postulates arrays of molecular markers, which are produced by specific cell types shortly after their final mitotic divisions and could be influential in the differentiation of other cell types. The second invokes a tangential dispersion of differentiating cells to generate spatial order, either while these cells are still migrating or soon after they reach their laminar destinations. The third involves the elimination of wrongly positioned cells through the process of naturally occurring cell death.

Segregation of on and off bipolar cell axonal arbors in the absence of retinal ganglion cells.

Retinal cells that respond selectively to light onset or offset are segregated into On and Off pathways. Here, we describe the development of cone bipolar cells whose axonal arbors at maturity synapse onto ganglion cell dendrites confined to On and Off strata of the inner plexiform layer (IPL). In particular, we sought to determine whether the formation of this segregated pattern is dependent on the presence of ganglion cells. Developing bipolar cells were visualized using an antibody against recoverin, the calcium binding protein that labels On and Off cone bipolar cells in the adult rat retina. Recoverin-positive cells were apparent in the ventricular zone on the day of birth [postnatal day 0 (P0)], before bipolar cells begin to migrate to the inner nuclear layer. Two distinct strata were first apparent in the IPL at P8, with the Off pathway maturing earlier than the On pathway. There was no indication of exuberant bipolar cell projections. Throughout development, there were also a small number of recoverin-positive cells of unknown origin in the ganglion cell layer. To assess whether the formation of On and Off cone bipolar cell projections is dependent on the presence of ganglion cells, these target neurons were eliminated by unilateral section of the optic nerve. This was done on the day of birth, resulting in a total loss of ganglion cells 5-6 d before bipolar cell axons innervate the IPL. In retinas with optic nerve sections, On and Off cone bipolar cells were present, albeit at a lower than normal density, and the axonal arbors of these interneurons were organized into two distinct strata. This indicates that ganglion cells are not essential for the formation of segregated On and Off bipolar cell inputs. These results lend support to the hypothesis that specific ingrowth patterns of bipolar cell terminal arbors could regulate the formation of stratified retinal ganglion cell dendrites.

Differential effects of apamin- and charybdotoxin-sensitive K+ conductances on spontaneous discharge patterns of developing retinal ganglion cells.

The spontaneous discharge patterns of developing retinal ganglion cells are thought to play a crucial role in the refinement of early retinofugal projections. To investigate the contributions of intrinsic membrane properties to the spontaneous activity of developing ganglion cells, we assessed the effects of blocking large and small calcium-activated potassium conductances on the temporal pattern of such discharges by means of patch-clamp recordings from the intact retina of developing ferrets. Application of apamin and charybdotoxin (CTX), which selectively block the small and large calcium-activated potassium channels, respectively, resulted in significant changes in spontaneous firings. In cells recorded from the oldest animals [postnatal day 30 (P30)-P45], which manifested relatively sustained discharge patterns, application of either blocker induced bursting activity. With CTX the bursts were highly periodic, short in duration, and of high frequency. In contrast, with apamin the interburst intervals were longer, less regular, and lower in overall spike frequency. These differences between the effects of the two blockers on spontaneous activity were documented by spectral analysis of discharge patterns. Filling cells from which recordings were made with Lucifer yellow revealed that these effects were obtained in all three morphological classes of cells: alpha, beta, and gamma. These findings provide the first evidence that apamin- and CTX-sensitive K+ conductances can have differential effects on the spontaneous discharge patterns of retinal ganglion cells. Remarkably, the bursts of activity obtained after apamin application in more mature neurons appeared very similar to the spontaneous bursting patterns observed in developing neurons. These findings suggest that the maturation of calcium-activated potassium channels, particularly the apamin-sensitive conductance, may contribute to the changes in spontaneous firings exhibited by retinal ganglion cells during the course of normal development.

Prenatal development of retinogeniculate axons in the macaque monkey during segregation of binocular inputs.

In the fetal monkey the projections from the two eyes are initially completely intermingled within the dorsal lateral geniculate nucleus (DLGN) before separating into eye-specific layers (). To assess the cellular basis of this developmental process, we examined the morphological properties of individual retinogeniculate axons in prenatal monkeys of known gestational ages. The period studied spanned the time from when binocular overlap has been reported to be maximum, circa embryonic (E) day 77 through E112, when the segregation process is already largely completed in the caudal portion of the nucleus. Retinogeniculate fibers were labeled by making small deposits of DiI crystals into the fixed optic tract. After adequate time was allowed for diffusion of the tracer, fibers were visualized by confocal microscopy, and morphometric measures were made from photomontages. This revealed that retinogeniculate fibers in the embryonic monkey undergo continuous growth and elaboration during binocular overlap and subsequent segregation. Importantly, very few side-branches were found along the preterminal axon throughout the developmental period studied. Thus, restructuring of retinogeniculate fibers does not underlie the formation of eye-restricted projections in the primate. Rather, the results support the hypothesis that binocular segregation in the embryonic monkey is caused by the loss of retinal fibers that initially innervate inappropriate territories ().

Blockade of glutamate-mediated activity in the developing retina perturbs the functional segregation of ON and OFF pathways.

The dendrites of ganglion cells initially ramify throughout the inner plexiform layer of the developing retina before becoming stratified into ON or OFF sublaminae. This ontogenetic event is thought to depend on glutamate-mediated afferent activity, because treating the developing retina with the glutamate analog 2-amino-4-phosphonobutyrate (APB), which hyperpolarizes ON cone bipolar cells and rod bipolar cells, thereby preventing their release of glutamate, effectively arrests the dendritic stratification process. To assess the functional consequences of this manipulation, extracellular recordings were made from single cells in the A laminae of the dorsal lateral geniculate nucleus and from the optic tract in mature cats that had received intraocular injections of APB during the first postnatal month. Such recordings revealed that stimulation of the APB-treated eye evoked both ON as well as OFF discharges in 37% of the cells tested. (As expected, when the normal eye was activated, virtually all cells yielded only ON or OFF responses.) The proportion of ON-OFF cells found here corresponds closely to the incidence of multistratified dendrites observed previously in anatomical studies of APB-treated cat retinas. This suggests that the ganglion cells with multistratified dendrites receive functional inputs from ON as well as OFF cone bipolar cells. This interpretation is further supported by the finding that the proportion of ON-OFF cells was very similar in the geniculate layer innervated by the treated eye and in the optic tract. The cells activated by the APB-treated eye were also found not to show response suppression when flashing stimuli of increasing size were used. This suggests that exposing the developing retina to APB perturbs the neural circuitry mediating the antagonistic center-surround organization found in normal receptive fields. The functional changes evident after treating the developing retina with APB suggest that it should now be feasible to assess how the segregation of ON and OFF retinal pathways relates to organizational features at higher levels of the visual system, such as orientation selectivity in cortical cells.

Activity-regulated cell death contributes to the formation of ON and OFF alpha ganglion cell mosaics.

At maturity, ON and OFF alpha ganglion cells in the cat retina are arrayed in regular mosaics, with adjacent cells commonly forming ON-OFF pairs. In the present study, we investigated the role of activity-mediated ganglion cell death in the formation of such cellular patterns. Because direct measures of ganglion cell mosaics are problematic in the developing retina, we examined the distributions of ON and OFF alpha cells in the postnatal cat retina by assessing the degree to which cells in closest proximity were of opposite sign (i.e., ON-OFF pairs). Computer simulations demonstrated that superimposition of two regular distributions results in a high incidence (approximately 90%) of opposite sign pairs. This is also the case for ON and OFF alpha cells in the mature retina, reflecting the high degree of regularity exhibited by this cell class. In contrast, during the first postnatal month, alpha cells displayed a much lower incidence of opposite sign pairs (approximately 60%), comparable to the superimposition of two simulated random distributions. We also show that there is a 20% loss of alpha cells in the central retina during postnatal development and that this magnitude of loss is sufficient to form regular distributions of ON and OFF cells. To assess the influence of sodium voltage-gated activity on this developmental process, intraocular injections of tetrodotoxin (TTX) were made during the postnatal period of alpha cell loss. When the TTX-treated animals reached maturity, there was a dose-related decrease in the incidence of opposite sign pairs, without any appreciable change in cell density. Moreover, the regularity index of ON and OFF cells was significantly lower than normal in the TTX-treated retinas. These findings demonstrate that a spatially selective pattern of ganglion cell loss contributes to the formation of regular ON and OFF ganglion cell distributions and that such cell loss is regulated by retinal activity.

Topographic specificity in the retinocollicular projection of the developing ferret: an anterograde tracing study.

To assess the degree of order exhibited during development by crossed and uncrossed retinocollicular pathways, focal deposits of 1,1'-dioctodecyl-3,3,3'3'-tetramethylinodocarbocyanine perchlorate (DiI) were made into the temporal or nasal retina of prenatal and postnatal ferrets. This procedure revealed that the first retinal fibers (from the ipsilateral temporal retina) grow into the superior colliculus at embryonic (E) day 30. Both crossed and uncrossed fibers innervate the colliculus by E34. At this age, terminal arbors were lacking, and there was no evidence of extensive axonal branching. Retinocollicular arbors first appeared at E38, with both the crossed and uncrossed projections forming well-defined terminal zones that appeared to be localized to topographically appropriate regions. At E38, the ipsilateral terminal zone was significantly larger but notably less dense than the contralateral zone. At this and later ages (postnatal day [P] 0 and P7), a few crossed and uncrossed fibers extended beyond the terminal zone. Four days later, at P0, the terminal zone of the uncrossed projection was reduced in size in comparison with that of earlier ages, whereas the crossed projection became substantially larger. By P7, the few misprojecting fibers seen in younger ferrets had been virtually eliminated. When focal retinal deposits of tracer were made into the nasal retina of E36 and E40 ferrets, crossed fibers were found to innervate the caudal segment of the superior colliculus. These crossed nasal cells appear to project to the topographically appropriate region of the superior colliculus (caudal segment) but on the wrong side of the brain. Collectively, the present findings indicate that throughout development the ferret retinocollicular pathway is characterized by a remarkable degree of topographic precision as evident by the paucity of axonal branches and the low number of grossly misprojecting axons.

Calcium-activated potassium conductances in retinal ganglion cells of the ferret.

Patch-clamp recordings were made from isolated and intact retinal ganglion cells (RGCs) of the ferret to examine the calcium-activated potassium channels expressed by these neurons and to determine their functional role in the generation of spikes and spiking patterns. Single-channel recordings from isolated neurons revealed the presence of two calcium-sensitive potassium channels that had conductances of 118 and 22 pS. The properties of these two channels were shown to be similar to those ascribed to the large-conductance calcium-activated potassium channel (BKCa) and small-conductance calcium-activated potassium channel (SKCa) channels in other neurons. Whole cell recordings from isolated RGCs showed that apamin and charybdotoxin (CTX), specific blockers of the SKCa and BKCa channels, respectively, resulted in a shortening of the time to threshold and a reduction in the hyperpolarization after the spike. Addition of these blockers also resulted in a significant increase in spike frequency over a wide range of maintained depolarizations. Similar effects of apamin and CTX were observed during current-clamp recordings from intact alpha and beta ganglion cells, morphologically identified after Lucifer yellow filling. About 20% of these neurons did not exhibit a sensitivity to either blocker, suggesting the presence of functionally distinct subgroups of alpha and beta RGCs on the basis of their intrinsic membrane properties. The expression of these calcium-activated potassium channels in the majority of alpha and beta cells provides a means by which the activity of these output neurons could be modulated by retinal neurochemicals.

The intrinsic temporal properties of alpha and beta retinal ganglion cells are equivalent.

BACKGROUND: Mammalian retinal ganglion cells have been traditionally classified on the basis of morphological and functional criteria, but as yet little is known about the intrinsic membrane properties of these neurons. This study has investigated these properties by making patch-clamp recordings from morphologically identified ganglion cells in the intact retina. RESULTS: The whole-cell configuration of the patch-clamp technique was used to assess the temporal tuning characteristics of alpha and beta cells, the two most extensively studied ganglion cell classes. Fourier analysis was used to examine discharge patterns in response to sinusoidal currents of different frequencies (1-50 Hz). With few exceptions, neurons responded in a stereotypic fashion to changes in temporal modulation, with their output initially increasing and then decreasing as a function of stimulus frequency. Moreover, peak responses in both cell classes were obtained at equivalent temporal frequencies. At high stimulus rates, response probability decreased, but the spikes remained phase-locked to the stimulus cycle, thereby enabling populations of cells to convey temporal information. A small number of ganglion cells did not show an appreciable decrease in output as a function of stimulus frequency, but these cells were not confined to either ganglion cell class. CONCLUSIONS: These findings provide the first evidence that the intrinsic temporal properties of alpha and beta cells are alike. Furthermore, the responses obtained to direct current injections were strikingly similar to those described previously with temporally modulated visual stimuli, suggesting that intrinsic membrane properties may shape the visual responses of alpha and beta cells to a larger degree than has been commonly assumed.

Early divergence of magnocellular and parvocellular functional subsystems in the embryonic primate visual system.

In both human and Old World primates visual information is conveyed by two parallel pathways: the magnocellular (M) and parvocellular (P) streams that project to separate layers of the lateral geniculate nucleus and are involved primarily in motion and color/form discrimination. The present study provides evidence that retinal ganglion cells in the macaque monkey embryo diverge into M and P subtypes soon after their last mitotic division and that optic axons project directly and selectively to either the M or P moieties of the developing lateral geniculate nucleus. Thus, initial M projections from the eyes overlap only in prospective layers 1 and 2, whereas initial P projections overlap within prospective layers 3-6. We suggest that the divergence of the M and P pathways requires developmental mechanisms different from those underlying competition-driven segregation of initially intermixed eye-specific domains in the primate visual system.

Functional development of intrinsic properties in ganglion cells of the mammalian retina.

Senosory neurons manifest pronounced changes in excitability during maturation, but the factors contributing to this ubiquitous developmental phenomenon are not well understood. To assess the contribution of intrinsic membrane properties to such changes in excitability, in the present study whole cell patch-clamp recordings were made from developing ganglion cells in the intact retina of postnatal rats. During a relatively brief developmental period (postnatal days P7-P27) ganglion cells exhibited pronounced changes in the discharge patterns generated by depolarizing current injections. The youngest cells (P7-P17) typically responded to maintained depolarizations with only a single spike or a rapidly adapting discharge pattern. In contrast, the predominant response mode of more mature cells (P21-P27) was a series of repetitive discharges that lasted for the duration of the depolarization period, and by P25 all cells responded in this manner. These functional changes characterized all three morphologically defined cell classes identified by intracellular labeling with Lucifer yellow. To determine if expression of the potassium current (Ia) and the kinetics of the Na-channel related to the increased excitability of developing ganglion cells described above, current- and voltage-clamp recordings were made from individual neurons. The different firing patterns manifested by developing retinal ganglion cells did not reflect the presence or absence of the Ia conductance, although cells expressing Ia tended to generate spikes of shorter duration. With maturation the speed of recovery from inactivation of the Na current increased markedly and this related to the increased excitability of developing ganglion cells. Neurons yielding only a single spike to maintained depolarization were characterized by the slowest speed of recovery; cells with rapidly adapting discharges showed a faster recovery and those capable of repetitive firing recovered fastest from Na-channel inactivation. It is suggested that these changes in intrinsic membrane properties may relate to the different functional roles subserved by ganglion cells during development.

The metabotropic glutamate agonist 2-amino-4-phosphonobutyric acid (APB) does not activate currents in postnatal retinal ganglion cells.

Whereas in the mature retina the glutamate agonist 2-amino-4-phosphonobutyric acid (APB) selectively activates currents in rod bipolar and ON-cone bipolar cells, recent molecular studies have suggested the possibility of a transient appearance of the APB-sensitive receptor in developing retinal ganglion cells. In the present study the whole-cell and perforated variations of the patch-clamp method were employed to assess the responsivity of postnatal cat retinal ganglion cells to APB. Recently, APB treatment has been shown in our laboratory to block the normal stratification of retinal ganglion cell dendrites into ON and OFF sublaminae of the inner plexiform layer. Although application of this glutamate agonist elicited inward sustained currents, amino acid analysis revealed that the APB product (RBI) was contaminated by 8% glycine. In subsequent experiments applications of uncontaminated APB (Cal Biochem) never yielded responses in postnatal retinal ganglion cells which displayed normal currents to other glutamate agonists. The findings do not support the notion of transient expression of APB receptors in retinal ganglion cells during the development period studied.

Topographic organization in the retinocollicular pathway of the fetal cat demonstrated by retrograde labeling of ganglion cells.

The topographic organization of the developing retinocollicular pathway was assessed by making focal deposits of a retrograde tracer (usually rhodamine latex beads) into the superficial layers of the superior colliculus of fetal cats at known gestational ages. Subsequently, the distributions of labeled cells in the contralateral and ipsilateral retinas were examined. At all stages of development, a high density of labeled cells was found in a delimited area (core region) of both retinas. The locations of the retinal regions containing the high density of labeled cells varied with the locus of the tracer deposit in the superior colliculus in a manner consistent with the topographic organization of the mature cat's retinocollicular pathway. Additionally, some labeled ganglion cells, considered to be ectopic, were found to be scattered throughout the contralateral and ipsilateral fetal retinas. Such ectopic cells were few in number throughout prenatal development. For every 100 cells projecting to the appropriate region of the colliculus, we estimate that less than one ganglion cell makes a gross projection error. The incidence of ectopic cells did not differ between the contralateral and ipsilateral retina, even though the overall density of crossed labeled cells was always greater than that of uncrossed labeled cells. In the youngest fetal animals, tracer deposits into the caudal portion of the superior colliculus resulted in a core region of labeled cells in the contralateral nasal retina as well as in the nasal ipsilateral retina. Such uncrossed nasal cells, not seen in more mature animals, appear to innervate the appropriate topographic location of the superior colliculus, but on the wrong side of the brain. Most likely, these uncrossed nasal ganglion cells contribute to the widespread distribution of the ipsilateral retinocollicular pathway observed in fetal cats after intraocular injections of anterograde tracers (Williams and Chalupa, 1982). Collectively, our findings demonstrate that the developing retinocollicular pathway of the fetal cat is characterized by a remarkable degree of topographic precision.

Specificity of retinal ganglion cell projections in the embryonic rhesus monkey.

Recent studies dealing with the organization of retinal projections in the developing rhesus monkey brain have revealed a high degree of developmental specificity. This is demonstrated by the ingrowth patterns of the initial contingents of crossed and uncrossed fibers that form the primordial optic tract as well as by the adult-like nasotemporal retinal decussation pattern evident even before the period of ganglion cell death. On the basis of these observations, it is suggested that early generated retinal fibers are guided through the optic chiasm by a transiently expressed decussation signal, and that later generated fibers utilize retinal position-dependent cues to innervate the appropriate hemisphere. Furthermore, the first retinal fibers to arrive at the dorsal lateral geniculate nucleus invade only the presumed parvocellular layers. Thus, the initial innervation of the lateral geniculate nucleus appears to reflect the birth order of retinal ganglion cell classes. It is suggested that the high degree of precision evident in the macaque monkey nasotemporal retinal decussation pattern relates to the adultlike distribution of callosal projection neurons in the developing striate cortex of the primate.