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Pharmacological modulation of on and off ganglion cells in the cat retina.

We studied the effects of 2-amino-4-phosphonobutyric acid and 2-amino-4-phosphonovaleric acid, which are antagonists to excitatory amino acids, on brisk-sustained(X) and brisk-transient(Y) ganglion cells in the cat retina. The ganglion cells were recorded extracellularly with a multibarreled electrode in the intact eye in vivo and drugs were applied iontophoretically. We found contrasting effects of 2-amino-4-phosphonobutyric acid and 2-amino-4-phosphonovaleric acid on ON- and OFF-centre cells irrespective of the brisk-sustained(X)/brisk-transient(Y) dichotomy. The maintained discharge and the light response of ON-centre cells decreased during 2-amino-4-phosphonobutyric acid and 2-amino-4-phosphonovaleric acid application, whereas the maintained discharge of OFF-centre cells increased. The light response of OFF-centre cells was not significantly affected. 2-Amino-4-phosphonovaleric acid was generally less potent than 2-amino-4-phosphonobutyric acid. It was shown in the mudpuppy retina [Slaughter and Miller (1981) Science, N.Y. 211, 182-185; Slaughter and Miller (1981) Invest. ophthal. Vis. Sci. 20, 44] that 2-amino-4-phosphonobutyric and 2-amino-4-phosphonovaleric acid selectively block the response of ON-bipolar cells. Assuming that these drugs act on the same synaptic sites in the cat retina, one expects a block of ON-centre ganglion cells. Moreover, the drug response of OFF-centre ganglion cells is then consistent with Sterling's hypothesis [Sterling (1983) A. Rev. Neurosci. 6, 149-185] that OFF-ganglion cells receive a direct inhibitory input from ON-bipolars. For some period 19 out of 108 cells responded to 2-amino-4-phosphonobutyric acid and 2-amino-4-phosphonovaleric acid in an opposite way to that described above: ON-centre cells increased and OFF-centre cells decreased their maintained discharge. It is proposed that this "reverse response" may be mediated by autoreceptors to excitatory amino acids or due to different receptor sites triggering antagonistic response mechanisms.

2-Amino-5-phosphonovalerate↗

Effects of dopamine and its agonists and antagonists on the receptive field properties of ganglion cells in the rabbit retina.

We investigated the effects of dopamine and its agonists and antagonists on the receptive field properties of ganglion cells in the isolated eyecup preparation of the rabbit. In general, dopamine (20-250 microM) reduced the overall sensitivity of ganglion cells to light stimuli while increasing the spontaneous activity of off-center cells and decreasing the spontaneous activity of on-center cells and on-off directionally selective cells. Neither(-)-apomorphine (8-82 microM) nor the selective D-2 agonist LY 141865 (7-85 microM) mimicked the effects of exogenous dopamine. Instead, both drugs altered the responses of ganglion cells in a manner similar to that of the selective D-1 antagonist SCH 23390. The latter at 4-41 microM: (1) selectively reduced the antagonistic surround responses of off-center cells; (2) changed the sustained excitatory responses of on-center sustained cells to spots of light into sustained inhibitory responses; (3) selectively reduced the leading edge responses of on-off directionally selective cells to moving light stimuli, and (4) decreased the spontaneous activity of off-center cells while increasing the spontaneous activity of on-center cells. The effects of the selective D-2 antagonist S-sulpiride (37-116 microM) on the responses of on-center cells resembled those of exogenous dopamine, while for off-center cells the effects of S-sulpiride were similar to those of (-)-apomorphine and LY 141865. Results were compared with those obtained previously with dopamine antagonists haloperidol, fluphenazine and cis-flupenthixol on ganglion cell responses in the intact rabbit eye. These three drugs were clearly acting at D-1 receptors. The present findings support a physiological role for D-2 receptors in visual processing in the rabbit retina, in particular the hypothesis that endogenous dopamine release is modulated by inhibitory D-2 autoreceptors. They also suggest that one function of dopaminergic neurons may be to modulate the sensitivity of ganglion cells to light stimuli.

Action Potentials↗

Transneuronal retrograde degeneration of retinal ganglion cells after damage to striate cortex in macaque monkeys: selective loss of P beta cells.

We examined the retinae of two monkeys whose left striate cortex had been removed eight years previously and compared the transneuronally degenerated hemiretina of each eye with the normal hemiretina, and with the retinae of normal monkeys. All retinae were prepared as whole mounts. One from each pair was stained with Cresyl Violet; the other was reacted for horseradish peroxidase two days after placing pellets of the enzyme in the optic nerve. Measurements of ganglion cell density in the Nissl-stained retina of the contralateral right eye showed that approximately 80% of retinal ganglion cells were missing in the central 30 degrees of the degenerated hemiretinae. More peripherally the percentage loss was less extensive. Measurements of cell soma size and dendritic field size of peroxidase-labelled classified surviving cells in the degenerated temporal hemiretina of the ipsilateral eye showed them to be morphologically normal. In comparison with the normal hemiretina, however, the mean soma size at three selected eccentricities was larger than normal, suggesting selective loss of smaller ganglion cells. Classification of peroxidase-labelled ganglion cells in the normal and degenerated hemiretinae revealed that the population of P beta cells was reduced by as much as 85% in the degenerated region. There was comparable change in the density of P alpha or P gamma cells. The degeneration of the great majority of P beta cells, which are believed to be the morphological substrate of ganglion cells with small and colour-opponent receptive fields, must set limits on the visual sensitivity and discrimination that survive damage to striate cortex.

Animals↗

Plasticity of tyrosine hydroxylase and vasoactive intestinal peptide messenger RNAs in visceral afferent neurons of the nodose ganglion upon axotomy-induced deafferentation.

The nodose ganglion contains placode-derived visceral sensory neurons of the vagus nerve. Previous study showed that axotomy-induced deafferentation reduced the number of tyrosine hydroxylase-immunoreactive and increased the number of vasoactive intestinal peptide-immunoreactive neurons in the ganglion. The present study was conducted to determine whether the changes in neuropeptide/neurotransmitter enzyme content are associated with changes in the expression of tyrosine hydroxylase and vasoactive intestinal peptide messenger RNAs in the nodose ganglion. We used in situ hybridization histochemistry with 35S-labeled oligonucleotide probes for tyrosine hydroxylase and vasoactive intestinal peptide precursor messenger RNAs. Peripheral axotomy of visceral afferent inputs reduced tyrosine hydroxylase messenger RNA and increased vasoactive intestinal peptide messenger RNA expression in neurons of the nodose ganglion of the rat. The number of tyrosine hydroxylase messenger RNA-containing neurons was significantly reduced at three, seven and 14 days after axotomy-induced deafferentation compared with intact and sham-operated controls. Labeling density of tyrosine hydroxylase messenger RNA-containing neurons was significantly reduced at three and seven days. Conversely, the number of vasoactive intestinal peptide messenger RNA-containing neurons increased significantly at three, seven and 14 days, while the labeling density of vasoactive intestinal peptide messenger RNA-containing neurons also increased at one, three, seven and 14 days. The results of the present study indicate that the axotomy-induced down-regulation of tyrosine hydroxylase and up-regulation of vasoactive intestinal peptide in the neurons of the nodose ganglion are associated with changes in their messenger RNAs in response to axotomy-induced deafferentation.

Animals↗

Stereotaxic atlas of the trigeminal ganglion in rat, cat, and monkey.

Stereotaxic maps of the trigeminal ganglion of rat, cat and monkey are presented. Each ganglion drawing is a composite from means of coordinates from several ganglions sampled. Depth coordinates are supplied in relation to both the dorsal surface of each ganglion and the cranial bone directly underlying the ganglion.

Animals↗

Type II cochlear ganglion cells in the chinchilla.

In order to ascertain whether Type II cochlear ganglion cells project to the brain, we have studied the retrograde transport of horseradish peroxidase (HRP) from the cochlear nucleus to the spiral ganglion of the chinchilla. In this animal there exist two types of ganglion neurons, which closely correspond to those previously described in guinea pigs, cats and rats. As in the guinea pig, the majority population (Type I) consists of relatively large, myelinated neurons. The minority population (Type II, 10% of the total population) consists of small, mostly unmyelinated cells, with filamentous cytoplasm and finely grained nuclear chromatin. Type II neurons tend to be clustered toward the peripheral side of Rosenthal's canal, often in close proximity to the intraganglionic spiral bundle. By 24 h after injections of HRP into the cochlear nucleus, incubation of the cochlear ganglion in diaminobenzidine/H2O2 reveals abundant HRP label in both Type I and Type II neurons. Type II neurons, however, tend to be labelled less intensely than Type I neurons. Control experiments, consisting of spillage of HRP solution over the cochlear nucleus, were carried out to determine how much HRP might be picked up by neurons after HRP diffusion. Comparison of cochleae from injected animals and from the control animals suggests that most of the label that was found in ganglion neurons after cochlear nucleus injections represents axonally transported HRP. We conclude, at least tentatively, that Type II neurons project to the brain. The fact that less label is found in Type II neurons that in Type I neurons suggests that the former have thinner axons and/or finer terminals in the cochlear nucleus.

Animals↗

Electrically-evoked responses in animals with progressive spiral ganglion degeneration.

The deafness (dn/dn) mouse has an hereditary cochlear dysfunction throughout its development, and spiral ganglion cell density decreases progressively over the three age groups we examined. We have used this mutant to examine inferior colliculus evoked responses to modiolar electrical stimulation as a function of spiral ganglion degeneration. No differences were found between mutants and control mice or between ages in either threshold for detection of the response or latency of the response. However, peak-to-peak amplitudes of the response were larger in the mutants than in the controls in the young and intermediate age groups. There was a poor correlation between spiral ganglion degeneration and size of the evoked response: for example, mutants in the old age group had similar amplitudes of response as controls while spiral ganglion cell density was reduced to 21% of the value in young mice, and mutants in the intermediate age group with 50% spiral ganglion degeneration showed response amplitudes more than double that in controls. These data may be relevant to the significant numbers of people with hereditary deafness among the hearing-impaired human population.

Aging↗

Degeneration of cochlear neurons as seen in the spiral ganglion of man.

A light and electron microscopic study of the spiral ganglion cells of a normal individual, a patient with Meniere's syndrome, and a patient with long-standing unilateral profound deafness was done to evaluate patterns of neural degeneration in the human inner ear. Parametric data for the normal spiral ganglion are presented and compared with the pathologic ganglia. In the ear with Meniere's syndrome, the nuclear area and axonic diameter of spiral ganglion cells were significantly smaller than in the contralateral and the normal ear. This was interpreted as evidence of neuronal degeneration in Meniere's syndrome. In the spiral ganglion of the long-standing deaf ear, there appeared to be selective preservation of large cells with no dendritic processes, contrary to the pattern of degeneration seen in the spiral ganglion of the animal.

Adult↗

Chronic intracochlear electrical stimulation induces selective survival of spiral ganglion neurons in neonatally deafened cats.

Ten newborn kittens were deafened by systemic administration of neomycin sulfate. Profound hearing losses were documented by ABR and FFR (500 Hz) testing. At 9-17 weeks of age, the young deafened cats were unilaterally implanted with a multichannel scala tympani electrode. Six of the animals were chronically stimulated at 6 dB above electrically evoked ABR thresholds for 1 h/day for periods of 1 month or 3 months. Stimuli were charge-balanced biphasic pulses (200 microseconds/phase, 30 pps.) The remaining 4 cats underwent identical deafening and implantation schedules but were not stimulated. Results indicate that administration of neomycin in neonatal cats induced degeneration of hair cells and spiral ganglion cell loss that was bilaterally symmetrical between the two cochleas of each individual animal, although there was variation between animals in the severity of the ototoxic drug effect. In animals receiving passive (unstimulated) implants, morphometric analysis of spiral ganglion cell density showed no significant difference in ganglion cell survival between the implanted cochleas and the contralateral control ears. In contrast, animals that were chronically stimulated for 3 months showed significantly better neuronal survival in implanted and stimulated cochleas as compared to contralateral deafened control ears. The induced conservation of spiral ganglion neurons was observed consistently within the basal cochlear region near the stimulating electrodes. In more apical regions there was no significant difference between the stimulated and control cochleas. The mechanisms underlying this selective conservation of spiral ganglion neurons induced by chronic intracochlear electrical stimulation are uncertain. Since no comparable chronic stimulation studies have been conducted in adults, it is not known whether similar conservation effects could be induced in mature animals.

Animals↗

Elevation of intracellular calcium levels in spiral ganglion cells by trimethyltin.

The neurotoxicant, trimethyltin (TMT) produces cochlear impairment at far lower dose levels and far more rapidly than it does central nervous system effects. The initial effects of TMT in the cochlea, in vivo, are consistent with disruption of the inner hair cell type-1 spiral ganglion cell synapse although it is uncertain whether the effect is on presynaptic and/or postsynaptic units. This synapse is believed to be an excitatory glutamatergic one, providing the possibility that TMT could induce an excitotoxic process resulting in elevations in intracellular calcium ([Ca2+]i). The objective of this study was to determine whether TMT had direct toxic effects on the postsynaptic spiral ganglion cells studied in primary culture and to identify the role of extracellular calcium in such an effect. The marker of interest was the effect of this agent on [Ca2+]i levels as determined using quantitation of the fluorescent calcium dye, Fura-2. TMT did induce a marked and sustained elevation in [Ca2+]i level in the spiral ganglion cells that appeared to have a rapid initial phase and a slower saturating phase. Studies performed using calcium-free medium showed that elevation of [Ca2+]i in spiral ganglion cells by TMT was attenuated but not entirely blocked. Further, the L-type calcium channel blocker, nifedipine, was able to inhibit the initial increase in [Ca2+]i, suggesting that at least this phase of the TMT effect was mediated by calcium channels, although nifedipine had no significant effect on the time to reach the maximal [Ca2+]i level. Parallel control experiments performed using application of exogenous glutamate and depolarizing K+ concentrations also produced elevation in [Ca2+]i levels. The data indicate that TMT elevates [Ca2+]i in isolated spiral ganglion cells both by increasing extracellular uptake via Ca2+ channels and also by releasing Ca2+ from intracellular stores. Thus TMT ototoxicity appears to include a direct postsynaptic toxic event.

Analysis of Variance↗

The use of the bovine retractor penis muscle for the assessment of ganglion-blocking activity of neuromuscular blocking and other drugs.

Inhibition of relaxation of strips of the bovine retractor penis muscle induced by a standard dose of nicotine (30 microM) was used for quantitative assessment of the ganglion-blocking activity of eight neuromuscular blocking agents that are in clinical use. The order of potency of the drugs studied was (+)-tubocurarine >> alcuronium > vecuronium > metocurine >> pancuronium > atracurium >>> suxamethonium > gallamine. The results have been compared to those obtained with other methods. On the basis of the present results, it is concluded that inhibition of the nicotine-induced relaxation of the bovine retractor penis muscle can be used as an alternative, sensitive in vitro method for the assessment of the ganglion-blocking activity of a neuromuscular blocking agent relative to that of, for example, (+)-tubocurarine. Earlier results have showed that this method is useful also for the assessment of the ganglion-blocking activity of other drugs, because it has yielded comparable and reproducible results at the quantitation of this property of actual ganglion-blocking and various antimuscarinic agents. In addition, this method may be useful for rapid screening of ganglion-blocking activity.

Animals↗

Use of ganglionic blockers to assess neurogenic pressor activity in conscious rats.

The present study was conducted to develop a standardized ganglionic blockade protocol to assess neurogenic pressor activity in conscious rats. Rats were instrumented with arterial and venous catheters for measurement of arterial pressure and heart rate and for administration of three different ganglionic blockers (trimethaphan, hexamethonium, and chlorisondamine). To investigate the role of the pressor hormones angiotensin II (AII) and arginine vasopressin (AVP) in modulating the cardiovascular responses to ganglionic blockade, we also administered ganglionic blockers to rats pretreated with AVP and AII receptor antagonists. The peak depressor responses to trimethaphan (20 mg/kg; -45 +/- 2 mm Hg), hexamethonium (20 mg/kg; -44 +/- 2 mm Hg), and chlorisondamine (2.5 mg/kg; -47 +/- 3 mm Hg) were not different from each other. With trimethaphan, there was a significantly enhanced peak depressor response after blockade of AT1/V1 receptors (-45 +/- 2 vs -59 +/- 2 mm Hg). No significant differences were observed for hexamethonium or chlorisondamine after hormonal blockade (-44 +/- 2 vs. -46 +/- 3 and -47 +/- 3 vs -48 +/- 4 mm Hg, respectively). These observations suggest that, for hexamethonium and chlorisondamine, the peak depressor response to ganglionic blockade is a consistent measure of neurogenic pressor activity in the conscious rat. This response is not influenced by circulating AII or AVP. On the other hand, trimethaphan should be used carefully due to its complex interactions with other systems, particularly under conditions in which AVP or AII may be altered.

Analysis of Variance↗

Large lateral meniscal ganglion cyst extending into the intercondylar fossa of the knee.

We report the case of a 31-year-old, otherwise healthy man with a large intra-articular meniscal ganglion cyst (27.7 x 13.5 mm) originating from the dorsal horn of the lateral meniscus. Clinically, the patient presented with knee pain in a squatting position. Magnetic resonance imaging revealed a large intra-articular cyst in the posterior compartment. At arthroscopic surgery, the ganglion cyst was found in the intercondylar space posteriorly to the posterior cruciate ligament. After removal of the ganglion cyst, a horizontal tear in the dorsal horn of the lateral meniscus was revealed and treated by partial meniscectomy. To our knowledge, a meniscal ganglion cyst originating from the lateral meniscus and extending into the joint is an extremely rare event, with only two previous reported cases. We review the current literature on the pathogenesis, distribution, and treatment of meniscal ganglion cysts.

Adult↗

Color information encoded by the spatiotemporal patterns of light response in ganglion cells of chick retina.

In the present study, the light responses of ganglion cells to chromatic stimulus were recorded from isolated retina of neonatal chick. It was found that for some non-color-opponent ganglion cells, the spatiotemporal patterns of the cells' light responses were related to the chromatic information that they received. When stimulus with some chromatic component was applied, some ganglion cells would generate distinguishable temporal patterns of light responses although these cells can be classified as non-color-opponent according to their light responses. The results suggest that in chick retina, the color information might be encoded not only by the color opponent ganglion cells, but also the spatiotemporal patterns of some ganglion cells that are traditionally classified as non-color-opponent subtype.

Action Potentials↗

Ganglion cell densities in normal and dark-reared turtle retinas.

In dark-reared, neonatal turtle retinas, ganglion cell receptive fields and dendritic trees grow faster than normal. As a result, their areas may become, on average, up to twice as large as in control retinas. This raises the question of whether the coverage factor of dark-reared ganglion cells is larger than normal. Alternatively, dark rearing may lead to smaller-than-normal cell densities by accelerating apoptosis. To test these alternatives, we investigated the effect of light deprivation on densities and soma sizes of turtle retinal ganglion cells. For this purpose, we marked these cells using retrograde labeling of fixed turtle retinas with DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate). Control turtles were maintained in a regular 12-h light/dark cycle from hatching until 4 weeks of age, whereas dark-reared turtles were maintained in total darkness for the same period. Ganglion cells in the control and dark-reared retinas were found to be similar in density and soma sizes. These results show that the mean coverage factor of turtle dark-reared ganglion cells is larger than normal.

Animals↗

Efficiency of information transmission by retinal ganglion cells.

BACKGROUND: Different types of retinal ganglion cells convey different messages to the brain. Messages are in the form of spike patterns, and the number of possible patterns per second sets the coding capacity. We asked if different ganglion cell types make equally efficient use of their coding capacity or whether efficiency depends on the message conveyed. RESULTS: We recorded spike trains from retinal ganglion cells in an in vitro preparation of the guinea pig retina. By calculating, for the observed spike rate, the number of possible spike patterns per second, we calculated coding capacity, and by counting the actual number of patterns, we estimated information rate. Cells with "brisk" responses, i.e., high firing rates, and a general message transmitted information at high rates (21 +/- 9 bits s(-1)). Cells with "sluggish" responses, i.e., lower firing rates, and specific messages (direction of motion, local-edge) transmitted information at lower rates (13 +/- 7 bits s(-1)). Yet, for every type of ganglion cell examined, the information rate was about one-third of coding capacity. For every ganglion cell, information rate was very close (within 4%) to that predicted from Poisson noise and the cell's actual time-modulated rate. CONCLUSIONS: Different messages are transmitted with similar efficiency. Efficiency is limited by temporal correlations, but correlations may be essential to improve decoding in the presence of irreducible noise.

Action Potentials↗

Changes in somatic sodium currents of ganglion cells during retinal regeneration in the adult newt.

Adult newts can regenerate their entire retinas following a complete removal of the original tissues. During retinal regeneration, ganglion cells differentiate first from the progenitor cells, and develop their capability of spike firing. In the present study, to understand the process of functional differentiation of ganglion cells, we investigated alterations of their voltage-gated sodium currents during retinal regeneration by a whole-cell patch-clamp technique. To minimize space clamp errors, sodium currents were recorded from neurite-free somata of presumptive ganglion cells that were mechanically isolated from living slices of regenerating retinas at different morphological stages. During retinal regeneration, the somatic sodium current density was increased 2.6-fold (48 to 123 pF/pA) and the half-activating voltage was shifted slightly to more hyperpolarizing membrane potentials (-10 to -13 mV), while steady-state inactivation was not changed obviously. Curve fitting analysis of currents revealed that the sodium current consists of two components with different inactivation time constants. During retinal regeneration, the ratio of slow to fast inactivating current component was increased 2.6-fold (0.11 to 0.29). These results suggest that the somatic sodium currents of ganglion cells may undergo modifications of their voltage dependence and kinetic properties during retinal regeneration. A small number of the presumptive ganglion cells in regenerating retinas with a segregating inner plexiform layer exhibited sodium currents comparable to those in the normal retina. This might suggest that maturational regulation of sodium channel function starts during a period of synaptic layer formation within the retina.

Action Potentials↗

Role of nonfeminizing estrogen analogues in neuroprotection of rat retinal ganglion cells against glutamate-induced cytotoxicity.

Glaucoma is a family of eye disorders whose ultimate cause of vision loss is apoptosis of retinal ganglion cells. Although several etiologies of glaucoma exist, oxidative stress is thought to be a key mechanism by which ganglion cells die. From this perspective, the work presented here was designed to examine the efficacy of 17beta-estradiol and three synthetic estrogen analogues (ZYC-1, ZYC-3, ZYC-10) as retinal ganglion cell neuroprotectants. Compound ZYC-1 and its enantiomer ZYC-10, containing an additional double bond in the steroid C ring of 17beta-estradiol, had similar (ZYC-1) or modestly reduced (ZYC-10) affinity for estrogen receptors compared to the parent estrogen. In the case of ZYC-3, the addition of an adamantyl group to the C2 position of the A ring of estrone abolished its binding to the estrogen receptors. RGC-5 cells (an established clonal rat retinal ganglion cell line) and rat retinas were shown to predominantly express estrogen receptor alpha, with minimal detectable levels of estrogen receptor beta. The affinity of the synthetic compounds for estrogen receptors was as follows: ZYC-3 < ZYC-10 < ZYC-1. An in vitro model of glutamate-induced RGC-5 cell death was used. Glutamate treatment resulted in 50-60% RGC-5 cell death with respect to control untreated cells. 17beta-estradiol and the three estrogen analogues (0.5 to 1.0 microM) protected the RGC-5 cells against glutamate cytotoxicity. The efficacy of neuroprotection by the estrogen analogues was as follows: ZYC-3 > ZYC-1 > ZYC-10. EC(50) values for inhibition of TBARS levels were as follows: ZYC-3 > ZYC-10 > ZYC-1. Furthermore, these compounds worked independent of estrogen receptors, as inclusion of 100 nM ICI 182,780 did not reverse their neuroprotective properties against glutamate insult. These compounds seem to affect neuroprotection via pathways independent of the classical estrogen receptors. The data support the hypothesis that estrogen analogues may be useful in the treatment of neurodegenerative diseases, particularly in neuroprotection of retinal ganglion cells in ocular pathologies such as glaucoma.

Animals↗