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The influence of postnatal neuronal activity on the magnitude of retinal ganglion cell death has been studied in cats. A constant blockade of activity in one eye starting just after birth does not change the severity of naturally occurring ganglion cell death, and as in normal animals, the ganglion cell population declines from 250,000 to 160,000 over a 4- to 6-week period. However, the population of retinal ganglion cells in the active untreated eye of monocularly deprived cats is increased 12% above normal (180,000 vs. 160,000 in each of four cases). This increase of 20,000 cells is permanent, and presumably reflects the competitive advantage in their target nuclei that the still active axons have over their silenced companions from the treated eye. Surprisingly, in one animal treated successfully for long duration with TTX in both from the population of ganglion cells was elevated in both eyes (200,000 and 208,000 ganglion cells). This increase matches that achieved by early unilateral enucleation (Williams et al., 1983). Our results demonstrate that the complete blockade of activity reduces the severity of naturally occurring cell death in a population of CNS sensory neurons. The effects of unilateral blockade emphasize that the activity-dependent modulation of neuron death only occurs under conditions that do not place the inactive population of neurons at a competitive disadvantage.

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To determine the cytochemical composition of presynaptic dendrites, we have examined the distribution of synapsin 1, calcium and calmodulin-dependent protein kinase II (CaM-II), microtubule-associated protein 2 (MAP-2) and spectrin in cat lateral geniculate (LGN) class III cells by immune-EM. Special attention was paid to the dendrites of these interneurons because they are both pre- and postsynaptic. The dendritic proteins MAP-2 and RBC spectrin were not observed in interneuron dendrites but these proteins were localized in relay cell dendrites. The synaptic vesicle-associated protein synapsin 1 was present in all synaptic vesicle containing profiles, including dendritic terminals. CaM-II, the major postsynaptic density protein, was found in all dendrites. Thus, the LGN interneuron dendritic compartment displays both axonal and dendritic cytochemical properties. The results suggest the possibility of unique molecular interactions in interneuron dendritic terminals.

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Although the influence of electrical activity on neural development has been studied extensively, experiments have only recently focused on the role of activity in the development of the mammalian central nervous system (CNS). Using tetrodotoxin (TTX) to abolish sodium-mediated action potentials, studies on the visual system show that impulse activity is essential both for the normal development of neuronal size and responsivity in the lateral geniculate nucleus (LGN), and for the eye-specific segregation of geniculo-cortical axons. There have been no anatomical studies to investigate the influence of action potentials on CNS synaptic development. We report here the first direct evidence that elimination of action potentials in the mammalian CNS blocks the growth of developing axon terminals and the formation of normal adult synaptic patterns. Our results show that when TTX is used to eliminate retinal ganglion-cell action potentials in the cat from birth to 8 weeks, the connections made by ganglion cell axons with LGN neurones, retinogeniculate synapses, remain almost identical morphologically to those in the newborn kitten.

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The role of action potentials in the development of proper synaptic connections in the mammalian CNS was studied in the kitten retinogeniculate pathway. Our basic finding is that there is improper segregation of retinal inputs onto LGN cells after prolonged retinal action-potential blockade. Retinal ganglion cell firing was silenced from birth by repeated monocular injections of TTX. The resulting ganglion cell connections in the LGN were studied electrophysiologically after the action-potential blockade was ended. Most cells in the deprived LGN layers received excitatory input from both ON-center and OFF-center type ganglion cells, whereas LGN cells normally receive inputs only from ON-center or OFF-center ganglion cells, but not from both types. Improper segregation of ON and OFF inputs has never been reported after other types of visual deprivation that do not block ganglion cell activity. Control experiments showed that receptive fields in the nondeprived LGN layers were normal, that ganglion cell responses remained normal, and that there was no obvious ganglion cell loss. We also showed that individual LGN cells with ON and OFF excitatory inputs were not present in normal neonatal kittens. Two other types of improper input segregation in response to action-potential blockade were also found in the deprived LGN layers. (1) A greater than normal number of LGN cells received both X- and Y-type ganglion cell input. (2) Almost half of the cells at LGN layer borders were excited binocularly. Recovery of LGN normality was rapid and complete after blockade that lasted for only 3 weeks from birth, but little recovery was seen after about 11 weeks of blockade. The susceptibility to action-potential blockade decreased during the first 3 postnatal weeks. These findings may result from axon-terminal sprouting or from the failure of axon terminals to retract. The results are consistent with the idea that normally synchronous activity of neighboring ganglion cells of like center-type may be used in the refinement of retinogeniculate synaptic connections.

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A previous study led us to consider the implications of the types of receptive fields found in the lateral geniculate nucleus (LGN) of neonatal kittens. Thus, we studied cells in the A layers in the LGN of kittens aged 6-29 days using extracellular recording techniques. Peri-stimulus-time-histograms were constructed in response to flashing spots of light centered in the receptive field of each unit. All units studied showed an excitatory response only to light onset (on-center) or light offset (off-center). No units were found which had an excitatory response to both phases of the stimulus (On-Off). Possible differences in classification between this study and that of earlier workers who reported On-Off cells in young kittens are discussed.

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The distributions of alpha-type ganglion cells in 3-week-old and adult cats were used to measure the increase in the distances between existing cells and thus the amount of growth in various regions of the retina. Growth shows two major non-uniformities. (1) The area centralis is at the point of minimum growth; its area increases by only about 3% while regions near the retinal margin increase in area by about 80%. (2) The retina grows about half as much in linear extent as does the radius of the eye and thus comes to occupy a smaller fraction of the globe. Measurements of retinal dimensions indicate that both non-uniformities also occur from birth to 3 weeks. These non-uniformities have the following implications. (1) They would tend to elongate dendritic fields radially, in the direction of the area centralis, in central retina but perpendicular to this direction in peripheral retina. However, these asymmetries are probably not the primary reason why ganglion cells throughout the retina tend to have radially oriented dendritic fields (Leventhal and Schall, '83). (2) Greater growth in the periphery could contribute to the gradient of increasing dendritic field size from central to peripheral retina if the dendritic fields of ganglion cells passively stretched as the retina expanded. Passive stretching is not the primary determinant of dendritic extent, however, because the dendritic fields of beta-type ganglion cells were found to grow 70% more from 3 weeks to adulthood than can be accounted for by passive stretching. (3) Greater peripheral growth steepens the central-to-peripheral gradient of decreasing ganglion cell density; if this trend also occurs prenatally, it could be the major factor in producing the final adult gradient.

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Under normal visual stimulation, simultaneous recording from ganglion cells in the retina and from the axons of these cells in the brain revealed activity-dependent differences in the velocity of impulse propagation. In frog ganglion cells, spikes initiated 5-500 ms after a previous impulse showed supernormal increases in conduction velocity of up to 17%; spikes initiated 500-2000 ms after a previous one traveled more slowly than a spike initiated after a long period of rest. Cat ganglion cell impulses showed much smaller supernormality (maximum 3%), but exhibited pronounced slowing due to refractoriness and long-term fatigue associated with their high levels of spontaneous activity.

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Action potentials were silenced in one eye of neonatal kittens by repeated intraocular injections of tetrodotoxin for 5 to 8 weeks. After tetrodotoxin blockade was allowed to wear off, receptive field properties of individual relay cells in the lateral geniculate nucleus were examined. The many ON-OFF and binocular fields found in the layers that receive input from the treated eye suggest that these cells had extremely abnormal retino-geniculate synaptic connections. These effects were different in kind from those seen after deprivation rearing that does not silence action potentials. Lack of action potential activity was concluded to lead to abnormal development in the central nervous system.

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This work investigated the function of interneurons and other types of cells in the lateral geniculate nucleus (LGN) in cats raised to adulthood with one eye sutured closed. In order to understand the basis of the commonly found deficit of Y-type relay cells in the deprived layers of the LGN, we looked for reduced or defective activity in other cells which also receive an afferent projection from Y-type ganglion cells in the visually deprived retina. Monocular deprivation did not produce a deficit in the activity of a class of interneurons which receive direct optic inputs from the same ganglion cells in the deprived eye that also drive the Y-type relay cells. Likewise, the Y-type afferent input from the deprived eye to XY-type relay cells was normal. The XY-type cells have mixed or hybrid receptive field properties and both X and Y excitatory inputs; although the Y-inputs to these cells are often much weaker than the X-inputs. The normal properties of Y-type interneurons and XY-type relay cells in the deprived LGN suggest that neither a retinal dysfunction nor an inherent inability of the Y-type optic tract axons to form adequate synapses onto LGN neurons are factors which would readily account for the reduction of Y-type relay cells in monocularly deprived cats. The hypothesis that the deprived Y-type relay cells may have difficulty in forming synaptic connections onto postsynaptic, binocular neurons was supported by observations of responses of cells in the perigeniculate region. Normally, perigeniculate neurons receive a strong binocular input from Y-type relay cells as well as an X-input in at least some cases. In binocular perigeniculate cells of the sutured cats, no inputs from deprived Y-type relay cells could be identified although a longer latency input, typical of that from X-type relay cells, was present.

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Postnatal neurogenesis in the kitten retina was studied using 3H-thymidine radioautography. Kittens were injected with 3H-thymidine at 1 day, 10 days, 3 weeks or 4 weeks after birth and allowed to survive until 14 weeks of age. Labeled neuronal nuclei were not found in the ganglion cell layer in any of the retinas, but they were seen in the other nuclear layers of the same retinas. In retinas from kittens injected at one day after birth, the peripheral 80% of the length of the retina (in sections cut parallel to the dorsoventral meridian) contained labeled nuclei; the central 20%, around the optic disc, contained no labeled nuclei. Near the ora serrata most nuclei in both inner and outer nuclear layers were labeled. Away from the ora serrata the proportion of labeled to unlabeled nuclei gradually decreased. Labeled nuclei extended farther centrally in the the inner than the outer nuclear layer. The same pattern of labeling was repeated in retinas from kittens injected at ten days after birth, but fewer nuclei were labeled, and the central, unlabeled region around the optic disc was longer--55% of the length of the retina. Only a few nuclei near the ora serrata were labeled in retinas from kittens injected at three weeks after birth, and no labeled neurons were found in kittens injected at four weeks. From these results we conclude that all of the ganglion cells in the kitten retina are present by one day after birth, as are all of the other neurons in the central retina. In peripheral regions of the inner and outer nuclear layers, proliferation of cells destined to become neurons continues up to three weeks after birth.

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A Golgi study of beta (brisk-X type) ganglion cells has been done to compare ganglion cells in the retina of 3-week-old and adult cats. An anatomical basis for the large receptive field centers found in the immature kitten retina was sought. Kitten beta-type ganglion cells have significantly smaller dendritic spreads than adult beta cells; the dendrites of the kitten cells must still grow to reach their final adult size. Therefore a synaptic basis for the large receptive field size of the immature cells is suggested.

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The retina of the normal pigmented mink has been studied by light and electron microscopy. This retina resembles the typical vertebrate retinia in its patterns of lamination and synaptic interconnectivity. Rod and cone outer segments and receptor spherule and pedicle endings are found. At least two different types of horizontal cell processes are seen with the electron microscope, suggestive of rabbit A and B types. Ribbon and conventional synapses are found in both plexiform layers; conventional synapses are also present in the inner nuclear layer. Quantitative studies of the inner plexiform layer revealed amacrine:bipolar synapse ratios (3.3:1) similar to those of the cat and monkey. Other quantitative parameters also resembled those previously reported for species with retinas that predominantly contain concentric-type receptive fields.

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1. Two groups of interneurons that are involved in the organization of the lateral geniculate nucleus (LGN) are described. The cell bodies of one group lie within the LGN; these units are referred to as intrageniculate. The cell bodies of the other group are found immediately above the LGN at its border with the perigeniculate nucleus; these units are referred to as perigeniculate. 2. Intrageniculate interneurons have center-surround receptive fields that resemble those of relay (principal) cells. They can be subdivided into brisk or sluggish and sustained or transient categories. They are stimulated transsynaptically from the visual cortex and have a characteristic variation in the latency of their spike response to such stimulation both at threshold and for suprathreshold stimuli. The pathway for this stimulation appears to be via cortical efferents to the LGN. Intrageniculate interneurons receive direct, monosynaptic retinal inputs, as determined by recording simultaneously from such interneurons and from the ganglion cells which provide excitatory input to them. Similar to relay cells, they are shown to have one or two major ganglion cell inputs. 3. Perigeniculate interneurons are generally binocularly innervated and give on-off responses to small spot stimuli throughout their receptive field. They respond well to rapid movement of large targets. They respond to electrical stimulation of the retina with a spike latency that falls between that of brisk transient and brisk sustained relay cells. This latency is one synaptic delay longer than that of brisk transient relay cell activation and suggests that they are excited by axon collaterals of these relay cells. Electrical stimulation of the visual cortex is also consistent with this model; the latency of the response of perigeniculate interneurons is approximately one synaptic delay longer than the latency of the response of brisk transient relay cells. 4. The interneuronal pathways described are consistent with proposed circuits that subserve the generation of IPSPs that arise in response to optic nerve and visual cortical stimulation. We now show that such inhibition has feed-forward (intrageniculate) and feed-back (perigeniculate) components that are mediated by two different classes of geniculate interneurons. It is suggested that the intrageniculate interneurons are involved in precise, spatially organized inhibition and that the perigeniculate interneurons are part of a more general, diffuse inhibitory system that modulates LGN excitability.

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In the retina of the frog and certain other animals, melanin pigment granules move in response to light so as to shield photoreceptor outer segments. The granules are contained within the cells of the pigment epithelium (PE) which lie as a continuous sheet between the neural retina and the choroid. Moderate illumination of the eye causes the melanin granules to move from a region within a PE cell body into numerous fingerlike extensions of the cell which interdigitate with the receptor outer segments. This migration takes many minutes and is reversed when the light falling on the eye increases in intensity. Several reviews are concerned with the early descriptions of this phenomenon (6,30) and with more recent experiments (1,5,19). The mechanism of the pigment granule motion is undetermined although there are studies concerning PE ultrastructure (8, 23, 31), scanning electron microscopy of the fingerlike extensions of the PE cells (27), the role of the PE in photoreceptor phagocytosis (32), the nature of the pigment granules (19), and the action spectrum of the light which induces the migration (16). This study reports the presence of a system of microfilaments associated with the pigment granules in the fingerlike extensions processes of the PE cells. We demonstrate by heavy meromyosin (HMM) labeling that the filaments are actinlike in character and suggest that these filaments could be responsible for the migration of the melanin pigment granules.

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1. Cat retinal ganglion cells may be subdivided into sustained and transient response-types by the application of a battery of simple tests based on responses to standing contrast, fine grating patterns, size and speed of contrasting targets, and on the presence or absence of the periphery effect. The classification is equivalent to the ;X'/;Y' (linear/nonlinear) subdivision of Enroth-Cugell & Robson which is thus confirmed and extended.2. The sustained/transient classification applied to both on-centre and off-centre cells.3. Lateral geniculate neurones may be similarly classified by the same tests. Occasional concentrically organized cells had a mixture of sustained and transient properties.4. A technique for simultaneous recording from a geniculate neurone and one or more retinal ganglion cells providing its excitatory input showed that the connexions were specific with respect to the sustained/transient classification as well as the on-centre/off-centre classification. Most geniculate neurones are excitatorily driven only by retinal ganglion cells of the same functional type. In a few cases the inputs were mixed but only with respect to the sustained/transient classification.5. Sustained retinal ganglion cells had slower-conducting axons than the transient type. The same was true for lateral geniculate neurones but in this case the distributions showed considerable overlap.6. The sustained/transient classification is the functional correlate for the well-known segregation of optic nerve fibres into two conduction groups.7. The pathways carrying sustained and transient information remain essentially separate from retina through the lateral geniculate nucleus to the striate cortex.

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