Reciprocal synaptic interactions between rod bipolar cells and amacrine cells in the rat retina.

Reciprocal synaptic transmission between rod bipolar cells and presumed A17 amacrine cells was studied by whole cell voltage-clamp recording of rod bipolar cells in a rat retinal slice preparation. Depolarization of a rod bipolar cell evoked two identifiable types of Ca2+ current, a T-type current that activated at about -70 mV and a current with L-type pharmacology that activated at about -50 mV. Depolarization to greater than or equal to -50 mV also evoked an increase in the frequency of postsynaptic currents (PSCs). The PSCs reversed at approximately ECl (the chloride equilibrium potential), followed changes in ECl, and were blocked by gamma-aminobutyric acidA (GABAA) and GABAC receptor antagonists and thus were identified as GABAergic inhibitory PSCs (IPSCs). Bipolar cells with cut axons displayed the T-type current but lacked an L-type current and depolarization-evoked IPSCs. Thus L-type Ca2+ channels are placed strategically at the axon terminals to mediate transmitter release from rod bipolar cells. The IPSCs were blocked by the non-N-methyl-D-aspartate (non-NMDA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, indicating that non-NMDA receptors mediate the feed-forward bipolar-to-amacrine excitation. The NMDA receptor antagonist 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid had no consistent effect on the depolarization-evoked IPSCs, indicating that activation of NMDA receptors is not essential for the feedforward excitation. Tetrodotoxin (a blocker of voltage-gated Na+ channels) reversibly suppressed the reciprocal response in some cells but not in others, indicating that graded potentials are sufficient for transmitter release from A17 amacrine cells, but suggesting that voltage-gated Na+ channels, under some conditions, can contribute to transmitter release.

Roles of N-methyl-D-aspartate receptors in ocular dominance plasticity in developing visual cortex: re-evaluation.

We have re-examined whether N-methyl-D-aspartate receptors play a specific role in experience-dependent plasticity in kitten visual cortex. A specific antagonist of this glutamate receptor subtype, D,L-2-amino-5-phosphonovaleric acid, was directly and continuously infused into kitten striate cortex for one week concurrently with monocular lid suture. In the hemisphere infused with 50 mM antagonist, we found the usual shift in ocular dominance toward the open eye with only a few binocular cells remaining. The changes were accompanied by an extremely high incidence (38%) of abnormal cells lacking orientation selectivity across different ocular dominance groups. In kitten cortex infused with 10 mM antagonist concurrently with monocular deprivation for a week, recording from a drug-affected region near the infusion centre, we again found the U-shaped ocular dominance distribution with the high incidence of non-selective cells. In antagonist-infused, otherwise normal striate cortex of adult cats, we found that the proportion of binocular cells decreased by one-half in two cellular populations: one recorded during the continuous infusion of 10 mM antagonist under general anaesthesia and paralysis, and the other about two days after stopping the infusion. We also established that in vivo concentrations of chronically infused 10 mM antagonist decreased, not near-exponentially, but linearly with increasing distance from the infusion site. Thus, the effects of a directly and continuously infused, concentrated antagonist of N-methyl-D-aspartate receptors on receptive-field properties of visuocortical cells are complex. The present findings strongly suggest that the antagonist effects in the developing cortex may be due primarily to blockade of normal synaptic transmission rather than specific disruption of an experience-dependent mechanism underlying ocular dominance plasticity.

Functional organization of cone bipolar cells in the rat retina.

The responses of cone bipolar cells in slices of rat retina to ionotropic glutamate receptor agonists were recorded with the whole cell voltage-clamp technique in the presence of 5 mM Co2+ and nominally 0 mM Ca2+ extracellularly. Application of the non-N-methyl-D-aspartate (non-NMDA) receptor agonists kainate and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate had a series of effects on cone bipolar cells (types 1-9), and the different cell types could be classified as ON- or OFF-type cells according to which type(s) of responses they displayed. First, direct responses were observed in cell types 1-4 as short-latency inward currents at -70 mV with reversal potentials (E(rev)s) close to 0 mV, characteristic of nonselective cation channels. Second, some cells, among types 5-9, did not display short-latency inward currents to kainate at -70 mV. Other type 5-8 cells displayed short-latency kainate responses, but the currents could not be reversed (E(rev) of +40 mV or greater). I suggest that these responses are conveyed to the cone bipolar cells through gap junctions, most likely with AII amacrine cells. The lack of reversal is likely due to a substantial voltage drop across the gap junctions resulting in an inadequate voltage control of AII amacrine cells when the recording pipette is on the cone bipolar cell. Kainate responses recorded directly from AII amacrine cells had E(rev) approximately 0 mV. Third, long-latency indirect responses selective for chloride ions (E(rev) approximately chloride equilibrium potential) were observed in many cone bipolar cells during longer-lasting application of kainate. The long-latency response component was suppressed by coapplication of the gamma-aminobutyric acid-A (GABA(A)) receptor antagonist picrotoxin and the GABA(C) receptor antagonist 3-aminopropyl(methyl)phosphinic acid. This long-latency component was absent in axotomized bipolar cells, suggesting that it was due to external Ca2+-independent release of GABA onto the axon terminals of the cone bipolar cells. All kainate-evoked response components were blocked by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Application of NMDA evoked no response in cone bipolar cells. These results suggest that cone bipolar cells types 1-4 are OFF cone bipolar cells, whereas cone bipolar cells types 5-9 are ON cone bipolar cells.

AII amacrine cells express functional NMDA receptors.

NMDA and non-NMDA receptors mediate the majority of fast excitatory synaptic transmission in the CNS. AII amacrine cells in the mammalian retina receive glutamatergic input from rod bipolar cells and are known to express non-NMDA receptors. We have investigated the expression of NMDA receptors in these cells by recording responses to exogenously applied NMDA in whole-cell recordings in slices of rat retina. Most cells displayed clear responses to NMDA. The responses could be blocked by a specific NMDA receptor antagonist and were characterized by voltage-dependent block with outward rectification. These results suggest that NMDA receptors could play a role in mediating excitatory synaptic input to AII amacrine cells.

Membrane currents evoked by ionotropic glutamate receptor agonists in rod bipolar cells in the rat retinal slice preparation.

1. With the use of the whole cell voltage-clamp technique, I have recorded the current responses to ionotropic glutamate receptor agonists of rod bipolar cells in vertical slices of rat retina. Rod bipolar cells constitute a single population of cells and were visualized by infrared differential interference contrast video microscopy. They were targeted by the position of their cell bodies in the inner nuclear layer and, after recording, were visualized in their entirety by labeling with the fluorescent dye Lucifer yellow, which was included in the recording pipette. To study current-voltage relationships of evoked currents, voltage-gated potassium currents were blocked by including Cs+ and tetraethylammonium+ in the recording pipette. 2. Pressure application of the non-N-methyl-D-aspartate (non-NMDA) receptor agonists kainate and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) from puffer pipettes evoked a long-latency conductance increase selective for chloride ions. When the intracellular chloride concentration was increased, the reversal potential changed, corresponding to the change in equilibrium potential for chloride. The response was evoked in the presence of 5 mM Co2+ and nominally O mM Ca2+ in the extracellular solution, presumably blocking all external Ca2(+)-dependent release of neurotransmitter. 3. The long latency of kainate-evoked currents in bipolar cells contrasted with the short-latency currents evoked by gamma-aminobutyric acid (GABA) and glycine in rod bipolar cells and by kainate in amacrine cells. 4. Application of NMDA evoked no response in rod bipolar cells. 5. Coapplication of AMPA with cyclothiazide, a blocker of agonist-evoked desensitization of AMPA receptors, enhanced the conductance increase compared with application of AMPA alone. Coapplication of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione blocked the response to kainate and AMPA, indicating that the response was mediated by conventional ionotropic glutamate receptors. 6. The conductance increase evoked by non-NMDA receptor agonists could not be blocked by a combination of 100 microM picrotoxin and 10 microM strychnine. Application of the GABAC receptor antagonist 3-aminopropyl (methyl)phosphinic acid (3-APMPA) strongly reduced the response, and coapplication of 500 microM 3-APMPA and 100 microM picrotoxin completely blocked the response. These results suggested that the conductance increase evoked by non-NMDA receptor agonists was mediated by release of GABA and activation of GABAC receptors, and most likely also GABAA receptors, on rod bipolar cells. 7. Kainate responses like those described above could not be evoked in bipolar cells in which the axon had been cut somewhere along its passage to the inner plexiform layer during the slicing procedure. This suggests that the response was dependent on the integrity of the axon terminal in the inner plexiform layer, known to receive GABAergic synaptic input from amacrine cells. 8. The results indicate that ionotropic glutamate receptors are not involved in mediating synaptic input from photoreceptors to rod bipolar cells and that an unconventional mechanism of GABA release from amacrine cells might operate in the inner plexiform layer.

Expression of the mRNA of seven metabotropic glutamate receptors (mGluR1 to 7) in the rat retina. An in situ hybridization study on tissue sections and isolated cells.

We have studied the expression of mRNAs for seven metabotropic glutamate receptors (mGluR1-7) in the retina of the adult rat by in situ hybridization with tissue sections and isolated cells using [alpha 35S]dATP-labelled oligonucleotide probes. Hybridization revealed the expression of six of the metabotropic receptor mRNAs, mGluR1, 2 and 4-7, in the retina, while mGluR3 was not detected. Each of the expressed receptor mRNAs showed a distinct pattern of expression. In the outer nuclear layer, corresponding to photoreceptor somata, no labelling was detected. In the outer part of the inner nuclear layer, putative horizontal cells were labelled for mGluR5. More proximal in this layer, corresponding to the position of bipolar cell somata, there was strong labelling for mGluR6. A small number of bipolar cells were also labelled for mGluR5 and mGluR7. In situ hybridization with isolated cells showed that mGluR6 was expressed by rod bipolar cells. Subsets of amacrine cells, with cell bodies along the border between the inner nuclear layer and the inner plexiform layer, were positive for mGluR1, 2, 4 and 7, suggesting considerable heterogeneity of these receptors among amacrine cells. None of the seven metabotropic receptor mRNAs was expressed in isolated Müller glial cells. In the ganglion cell layer, virtually every ganglion cell and displaced amacrine cell was labelled for mGluR1 and mGluR4. Some cells in this layer (approximately 20% of the total), most likely both ganglion cells and displaced amacrine cells, were also labelled for mGluR2 and mGluR7. These findings suggest that metabotropic glutamate receptors are considerably more widespread among neurons in the retina than indicated by previous physiological and pharmacological investigations.

Expression of GABA receptor rho 1 and rho 2 subunits in the retina and brain of the rat.

We have investigated the distribution of GABA receptor rho 1 and rho 2 subunits in the rat central nervous system. Cloning of rat rho 1 and rho 2 cDNA fragments revealed similarities to the corresponding human sequences of 99% (rho 1) and 88% (rho 2) at the protein level. Whereas the human rho 2 subunit has no consensus sequence for phosphorylation by protein kinase C, the cytoplasmic loop of the rat sequence contains two such sites. Use of the polymerase chain reaction with reverse-transcribed total RNA (RT-PCR) from different brain tissues revealed that transcript for the rho 1 subunit was present in the retina only. The rho 2 mRNA was detected in all brain regions, with the highest level of expression in the retina. In situ hybridization of retinal sections revealed that rho 1 and rho 2 transcripts are present in the inner nuclear layer. RT-PCR and in situ hybridization of isolated retinal cells showed that both rho subunits are present in rod bipolar cells. Since these cells express bicuculline-insensitive GABA receptors, our results further support the idea that rho subunits are part of the GABAc receptor.

Brainstem modulation of signal transmission through the cat dorsal lateral geniculate nucleus.

We studied changes in retinogeniculate transmission that occur during variation of modulatory brainstem input and during variation of stimulus contrast. Responses of single cells in the dorsal lateral geniculate nucleus (dLGN) to a stationary flashing light spot of varying contrast were measured with and without electrical stimulation of the peribrachial region (PBR) of the brainstem. PBR stimulation increased the contrast gain (slope of response versus contrast curve) and the dynamic response range (range between spontaneous activity and maximal firing). Lagged and nonlagged X-cells reached the midpoint of the dynamic response range at lower contrasts during PBR stimulation than in the controls. No comparable change was seen for Y-cells. Only minor changes of threshold contrast were seen. The characteristics of the retinogeniculate transmission were directly studied by comparing the response of dLGN cells with their retinal input (slow potentials, S-potentials). With increasing contrast there was a marked increase in the transfer ratio (proportion of impulses in the input that generates action potentials in the dLGN cell). The transfer ratio seemed to be primarily determined by the firing rate of the retinal input. The transfer ratio increased with increasing input rates from low values near threshold to values that could approach 1 at high-input firing rates. PBR stimulation increased the transfer ratio, particularly at moderate input firing rates. The increased transfer ratio, caused by increasing input firing rates, enhanced the response versus contrast characteristics through an increase in contrast gain and dynamic response range. The modulatory input from the PBR further enhanced these characteristics.

Localization and developmental expression of the NMDA receptor subunit NR2A in the mammalian retina.

The localization of the N-methyl-D-aspartate receptor subunit NR2A was studied, by using light microscopic immunocytochemistry, in the retina of adult rat, rabbit, cat, and monkey. Strong, punctate immunolabeling was observed in the inner plexiform layer indicating a synaptic localization of the NR2A subunit. The punctate labeling was concentrated in two bands corresponding to the on- and off-sublaminae of the inner plexiform layer. The punctate character of immunofluorescence suggested a synaptic localization of the receptor. This was confirmed by electron microscopy of immunostained adult rat retina. The staining was localized postsynaptic to cone bipolar cells, and only one of the two postsynaptic elements of the dyad was labeled. Staining was not observed at extrasynaptic plasma membranes. In situ hybridization of adult rat retina showed expression of the NR2A subunit in virtually all ganglion cells and displaced amacrine cells in the ganglion cell layer and in a subset of amacrine cells in the inner nuclear layer. The postnatal developmental expression of the NR2A subunit was studied in rat retina by light microscopic immunocytochemistry. Punctate immunolabeling appeared prior to eye opening, and the developmental profile of NR2A could be compatible with a role in development of circuitry in the inner plexiform layer.

Response variability of single cells in the dorsal lateral geniculate nucleus of the cat. Comparison with retinal input and effect of brain stem stimulation.

1. We studied the degree and source of response variability in different classes of cell in the dorsal lateral geniculate nucleus (dLGN). The response of single cells to a series of contrasts of a stationary flashing light spot was measured. The variability analyses were based on the mean and SD of the response to a number of repeated stimulus presentations. The relative variability was expressed by the coefficient of variation (Cv; SD/mean). 2. At a given contrast, the Cv for lagged cells was larger than for nonlagged cells. No difference was found between the Cv of X and Y cells. The magnitude of the Cv was about the same as previously found for cells in striate cortex. Accordingly, little variability is added at the cortical level. The Cv decreased with increasing contrast showing that the reliability of response and the signal-to-noise ratio was improved with increasing contrast. 3. For some cells, the retinal input was determined by recording S potentials in addition to action potentials. The Cv of the retinal input was smaller than the Cv of the dLGN cells at a given contrast. Thus in the paralyzed and anesthetized preparation, variability was added at the geniculate relay. 4. The additional variability was related to modulatory input from the brain stem. This was shown by comparing Cv versus contrast curves for the dLGN cells obtained during electrical stimulation of the peribrachial region of the brain stem (PBR) with corresponding curves obtained without PBR stimulation. During PBR stimulation, which presumably mimics the effects of arousal on the dLGN cell, the Cv at a given contrast was reduced toward the value for the retinal input to the cell. Furthermore PBR stimulation increased the signal-to-noise-ratio of the cell to the level of the retinal input. 5. When Cv was plotted against response rather than against contrast, approximately the same function was found for the various dLGN cell classes. This indicated that the variability basically depended on firing rate rather than on stimulus contrast. No difference of Cv was seen between lagged and nonlagged cells at a given level of response. The difference found at a given level of contrast reflected differences in firing rate of the two cell classes. During PBR stimulation, there was no clear difference between the Cvs of the dLGN cell and its retinal input at a given level of response.(ABSTRACT TRUNCATED AT 400 WORDS)

Expression of NMDA and high-affinity kainate receptor subunit mRNAs in the adult rat retina.

The expression patterns of nine genes encoding the N-methyl-D-aspartate (NMDA) receptor subunits NR1 and NR2A, NR2B, NR2C and NR2D, and the high-affinity kainate receptor subunits KA1, KA2, GluR6 and GluR7, were studied in the adult rat retina by in situ hybridization. Hybridization with [35S]dATP-labelled oligonucleotide probes revealed the expression of four of the NMDA receptor subunits (NR1, NR2A, NR2B and NR2C) and three of the high-affinity kainate receptor subunits (KA2, GluR6 and GluR7) in the retina. The NMDA receptor subunit NR2D and the high-affinity kainate receptor subunit KA1 could not be detected. In the ganglion cell layer, virtually every ganglion cell or displaced amacrine cell expressed the receptor subunits NR1, NR2A, NR2B, NR2C, KA2 and GluR7. The GluR6 subunit was expressed in a more restricted manner in the ganglion cell layer. In the inner nuclear layer, the receptor subunits NR1 and KA2 were homogeneously distributed, and therefore are most likely expressed by all cell types in this layer. The GluR6, NR2A, NR2B and NR2C subunits were expressed by subsets of amacrine cells. Labelling for NR2C was also found above the middle of the inner nuclear layer, corresponding to the location of bipolar cell somata. The GluR7 subunit was expressed by most amacrine and bipolar cells. These findings suggest that NMDA and high-affinity kainate receptor subunits could be present at a majority of glutamatergic retinal synapses.

Brain stem modulation of spatial receptive field properties of single cells in the dorsal lateral geniculate nucleus of the cat.

1. We studied the effect of electrical stimulation of the peribrachial region (PBR) in the brain stem on the visual response of single cells in the dorsal lateral geniculate nucleus (dLGN) to a light slit presented in a series of positions across the receptive field. The response was plotted against slit position, giving a spatial receptive field profile. 2. PBR stimulation markedly increased the visual response. In the middle of the receptive field center, the absolute response increase was considerably larger than in the peripheral parts of the receptive field or than the increase of spontaneous activity. The PBR stimulation also led to a small increase of the diameter of the receptive field center. 3. The maximum steepness of the receptive field profile for the dLGN cells increased by PBR stimulation. We suggest that the visual resolution in the dLGN cell is directly related to this maximal slope of the receptive field profile rather than to the width of the receptive field center. This would mean that increased input from the PBR, as presumably occurs during arousal, increases the visual resolution of the dLGN cells. 4. For some of the cells we could record S-potentials (slow potentials) in addition to action potentials. This allowed us to directly compared the receptive field center size of a dLGN cell with that of its retinal input. For these cells, the center size was considerably reduced by the geniculate relay. During PBR stimulation, the center size of these cells also increased slightly, but even in this condition it was reduced compared with the retinal input. The maximal slope of the receptive field profile in the dLGN cell during PBR stimulation was larger than for the retinal input. 5. We also examined the effect of ionophoretical application of acetylcholine (ACh) and bicuculline methchloride (BMC) on the spatial receptive field properties of dLGN cells. The effects of ACh were similar to those of PBR stimulation. Application of BMC, on the other hand, made the receptive field profile more similar to that of retinal ganglion cells.

Brain-stem influence on visual response of lagged and nonlagged cells in the cat lateral geniculate nucleus.

This study examined the influence of the pontomesencephalic peribrachial region (PBR) on the visual response properties of cells in the dorsal lateral geniculate nucleus (LGN). The response of single cells to a stationary flashing light spot was recorded with accompanying electrical stimulation of the PBR. The major objectives were to compare the effects of PBR stimulation on lagged and nonlagged cells, to examine how the visual response pattern of lagged cells could be modified by PBR stimulation and to examine whether the physiological criteria used to classify lagged and nonlagged cells are applicable during increased PBR input to the LGN. During PBR stimulation, the visual response was enhanced to a similar degree for lagged and nonlagged cells and the latency to half-rise of the visual response was reduced, particularly for the lagged X cells. The latency to half-fall of the visual response of lagged cells was not changed by PBR stimulation. Accordingly, the division of LGN cells into lagged and nonlagged cells based on visual response latencies was maintained during PBR stimulation. The initial suppression that a visual stimulus evokes in lagged cells was resistant to the effects of PBR stimulation. For the lagged cells, the largest response increase occurred for the initial part of the visual response. For the nonlagged cells, the largest increase occurred for the tonic part of the response. The results support the hypothesis that the differences in temporal response properties between lagged and nonlagged cells belong to the basic distinctions between these cell classes.

The effect of acetylcholine on the visual response of lagged cells in the cat dorsal lateral geniculate nucleus.

We examined the influence of acetylcholine (ACh) on the visual response properties of lagged cells in the dorsal lateral geniculate nucleus of anaesthetised cats. By means of electrophysiological techniques, the response of single cells was recorded before, during and after ionophoretic application of ACh. ACh evoked a clear enhancement of the visual response. The initial suppression that a visual stimulus evokes in lagged cells was resistant to the effects of ACh. The characteristic anomalous response component of lagged cells was also present during application of ACh. The difference in latency to half-rise and to half-fall of the visual response that is found between lagged and non-lagged cells was maintained during application of ACh. Taken together, the results support previous evidence from experiments with brain stem stimulation that the fundamental visual response characteristics of lagged cells are state independent.

The effect of contrast on the visual response of lagged and nonlagged cells in the cat lateral geniculate nucleus.

The response vs. contrast characteristics of different cell classes in the dorsal lateral geniculate nucleus (LGN) were compared. The luminance of a stationary flashing light spot was varied stepwise while the background luminance was constant. Lagged X cells had lower slope of the response vs. contrast curve (contrast gain), and they reached the midpoint of the response range over which the cells' response varied (dynamic response range) at higher contrast than nonlagged X cells. These results indicated that nonlagged cells are well suited for detection of small contrasts, whereas lagged cells may discriminate between contrasts over a larger range. The contrast gain and the contrast corresponding to the midpoint of the dynamic response range were similar for X and Y cells. The latency to onset and to half-rise of the visual response decreased with increasing contrast, most pronounced for lagged cells. Even at the highest contrasts, the latency of lagged cells remained longer than for nonlagged cells. For many lagged cells, the latency to half-fall decreased with increasing contrast. It is shown that the differences in the response vs. contrast characteristics between lagged and nonlagged X cells in the cat are similar to the differences between the parvocellular and magnocellular neurones in the monkey.

Simultaneous recording of lagged and nonlagged cells in the cat dorsal lateral geniculate nucleus.

It has been suggested that lagged and non-lagged cells in the cat dorsal lateral geniculate nucleus (LGN) represent state-dependent response modes of the same class of LGN cells. In two separate experiments with single-unit recording in the LGN of anaesthetized and paralysed adult cats, a lagged and a nonlagged X-cell were recorded simultaneously with the same microelectrode. For each pair of cells, the amplitude of the action potentials was sufficiently different to allow separate compilation of peri-stimulus-time-histograms. For all 4 cells, the visual response pattern to a stationary flashing light spot was typical of their respective cell class. These findings support the hypothesis that lagged and non-lagged cells are separate cell classes and indicate that the population of LGN cells do not appear as lagged during one state of modulatory input and as nonlagged during another.

Attenuated cells in breast stroma: the missing lymphatic system of the breast.

The breast stroma, in association with normal and neoplastic epithelium, is shown to contain cells of similar ultrastructure to the fine lymphatic vessels and sinusoids described in detail in the literature on other organs. As in other organs, the lumen of these structures is in continuity with the tissue spaces, allowing a free flow of lymph and its content, fluid and cells, from the tissues to the drainage system. The lymphatic system is, thus, open-ended-the endothelial cells of its finest branches having overlapping junctions that open passively on demand. There is, therefore, no need to postulate that cancer cells actively invade the surrounding tissues. In addition, the breast stroma contains endothelial cells in which the luminal side is not apposed to that of the same or another endothelial cell. These, like other endothelial cells, are attached to the connective tissue elements on one side only. It is suggested that they provide a series of potential spaces that can conduct fluid rapidly through the tissues, providing the epithelial cells with a copious supply of nutrients. This irrigation system is termed the lymphatic labyrinth, to distinguish it from the classical sinusoids and collecting vessels of the drainage system.

Neurotransmitter receptors mediating excitatory input to cells in the cat lateral geniculate nucleus. I. Lagged cells.

1. Synaptic mechanisms that might explain the functional properties of the recently discovered class of lagged cells in the dorsal lateral geniculate nucleus (LGN) were analyzed with electrophysiological and pharmacologic techniques. To study the type of excitatory amino acid (EAA) receptor that mediates visual responses of lagged cells, we recorded the response of single cells to a stationary flashing light spot before, during, and after microiontophoretic application of antagonists and agonists to EAA receptors. 2. The visual response of the lagged cells could be almost completely blocked by an antagonist to the N-methyl-D-aspartate (NMDA) receptor. The degree of suppression was dose dependent, and the average maximum degree of suppression for all the cells was 94%. NMDA enhanced the response, and this enhancement was antagonized by NMDA antagonists. A quisqualate/kainate receptor antagonist had no significant effect on the lagged cells. 3. These findings indicate that the visual response in lagged cells is dependent upon activation of NMDA receptors, which may directly result from activation of retinal inputs. 4. No pharmacologic difference was seen between lagged X- and Y-cells, or between lagged ON- and OFF-center cells. 5. gamma-Aminobutyric acid-A (GABA-A) receptor antagonists were used to study whether the characteristic lag of the visual response and the suppression of the initial transient response component of the lagged cells are dependent on geniculate inhibition. Beside enhancement of the visual response, the GABA antagonists strongly reduced the lag of the visual response, and an initial transient response component occurred instead of the initial suppression. The lag remained slightly longer than for nonlagged cells, and the peak firing rate of the transient was below values typical for nonlagged cells, indicating that the lagged cell properties are dependent on other factors beside GABA-A receptor-mediated inhibition. 6. The enhanced visual response during iontophoresis of GABA antagonists could be completely blocked by simultaneous iontophoresis of an NMDA-receptor antagonist. This gives further support to the hypothesis that the retinal input to these cells is mediated by NMDA receptors. 7. The NMDA-receptor/ionophore complex mediates excitatory postsynaptic potentials (EPSPs) characterized by slow rise and decay times and long duration. The ionophore is characterized by a voltage-dependent blockade that makes these receptors particularly sensitive to inhibitory input. The temporal interplay between the slow NMDA receptor-mediated EPSPs and the fast GABA receptor-mediated inhibitory postsynaptic potentials (IPSPs) may explain the characteristic response properties of the lagged cells.

Neurotransmitter receptors mediating excitatory input to cells in the cat lateral geniculate nucleus. II. Nonlagged cells.

1. We studied the type of receptor for excitatory amino acids (EAA) that mediates visual responses of nonlagged cells in the dorsal lateral geniculate nucleus (LGN) by recording the visual response of single cells to a stationary flashing spot before, during, and after iontophoretical application of antagonists and agonists to EAA receptors. 2. The visual response of the nonlagged cells was strongly suppressed, in a dose-dependent manner, by the specific quisqualate/kainate receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). The average degree of suppression was 74%. Quisqualate enhanced the visual response. 3. Specific antagonists to the N-methyl-D-aspartate (NMDA) receptor had a weak suppressing effect on most nonlagged cells. The average degree of suppression was 22%. Measurement of such weak effects was complicated by the considerable spontaneous fluctuations of responsivity in the LGN cells. In the majority of cells where the visual response was suppressed by NMDA antagonists, the tonic response component was more strongly suppressed than the initial transient response component. The visual response was enhanced by NMDA, and this enhancement was antagonized by NMDA antagonists. 4. These findings suggest that the excitatory input from the retina to nonlagged LGN cells is mainly mediated by non-NMDA receptors. The non-NMDA receptors mediate fast EPSPs, and this can explain the fast onset and offset of the visual response of the nonlagged cells. 5. The generally small contribution from NMDA receptors to the visual response of the nonlagged cells might reflect a minor involvement of these receptors in the retinal input, or it could be related to the excitatory input to LGN from the visual cortex. 6. To study whether the expression of NMDA receptors was related to modulatory brain stem input to LGN, we examined the effects of the NMDA antagonists when the visual response was enhanced with gamma-aminobutyric acid (GABA) antagonists or acetylcholine (ACh). Neither of these pharmacologic manipulations consistently increased the relative contribution of NMDA receptors to the visual response. 7. No pharmacologic difference was found between nonlagged X- and Y-cells, or between ON- and OFF-center cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Side and survival in breast cancer.

In recent years changes have occurred in the 5-year survival pattern and relative side distribution of operable breast carcinoma in this district. The 87 cases from 1970 showed the expected pattern; node-negative cases doing better than node-positive, irrespective of side. In 163 cases from the same population given similar treatment in 1975 those with left-sided disease fared better, irrespective of nodal status. No side differences were found at operation in the 1970 group, and little evidence of such changes in 1975, but clear differences were present in a third group of 63 patients from 1980. It is suggested that women in this district are becoming consistently more successful at finding their tumours, particularly on the left. It may thus be advisable to include side as a discriminant in clinical trials.