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The Journal of Neurophysiology Vol. 81 No. 1 January 1999, pp. 204-215
Copyright ©1999 by the American Physiological Society
Department of Ophthalmology and Visual Science, Yale University Medical School, New Haven, Connecticut 06520-8061
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Daw, N. W., B. Gordon, K. D. Fox, H. J. Flavin, J. D. Kirsch, C. J. Beaver, Q.-H. Ji, S.N.M. Reid, and D. Czepita. Injection of MK-801 affects ocular dominance shifts more than visual activity. J. Neurophysiol. 81: 204-215, 1999. Kittens were given intramuscular injections of the N-methyl-D-aspartate (NMDA) antagonist MK-801 twice daily (morning and midday) during the peak of the period of susceptibility for ocular dominance changes. They were then exposed to light with one eye closed for 4 h after each injection. The ocular dominance of these kittens was shifted significantly less than that of kittens injected with saline and exposed to light over the same period at the same age. After recording a sample of cells for an ocular dominance histogram, the kittens were injected with the same dose of MK-801 that was used during rearing to observe its effect on the activity of single cells in the visual cortex. In the majority of cells (7/13) there was no significant change in activity. Positive evidence for a reduction in activity was seen in only a minority (3/13) of cells. In a separate series of experiments, dose-response curves were measured for cells in the visual cortex in response to iontophoresis of NMDA or 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and the effect of an injection of MK-801 on these curves was measured. MK-801, at doses similar to those used in the ocular dominance experiments, had a significant effect on the dose-response curves for NMDA, but little effect on the dose-response curves for AMPA, or the visual responses of the cells. We conclude that ocular dominance shifts can be reduced significantly by a treatment that has little effect on the level of activity of cells in the visual cortex but does specifically affect the responses of the cells to NMDA as opposed to the responses to AMPA.
Permanent irreversible changes occur in the visual cortex when the visual input is restricted early in life (Wiesel 1982 General procedure
Treatment was started at 4-51/2 wk of age (Table 1). The eyelids of the right eye were sutured closed. The animal was then exposed to light for 8 h/day for 5 days in the first series of experiments and for 8 days in the second. It was kept in the dark with its mother at all other times until the day of recording.
MD
Eyelids were sutured together under anesthesia with ketamine (20-30 mg/kg im) and xylazine (0.5 mg/kg im). One drop of proparacaine hydrochloride (Alcaine) was dropped onto the cornea. The lid margins were then cut. Polymyxin b-bacitracin-neomycin (Neosporin) eye ointment was placed between the eyelids, which were then sutured together with 4-0 thread, leaving a small aperture at the medial edge for drainage. Sutures were inspected daily to make sure that they were healing and that no holes appeared.
Preparation for physiology
Animals were sedated with acepromazine, 0.1 mg/kg im (Fermentia Animal Health, Kansas City, MO), and given a preanesthetic dose of atropine, 0.04 mg/kg im. Anesthesia was induced with 4% halothane in a mixture of 67% nitrous oxide-33% oxygen and maintained with 0.5-0.9% halothane. After tracheotomy and insertion of an intravenous cannula into the femoral vein, the skull was opened over the lateral gyrus, and a small hole was made in the dura for insertion of the electrode. All wound margins were treated with local anesthetic (Lidocaine). After surgery, the animal was paralyzed by intravenous infusion of pancuronium bromide at 0.6-1.5 mg/h (Elkins-Sinn, Cherry Hill, NJ). Body temperature was maintained at 37.5°C with a heating pad controlled by a rectal thermometer. Heart rate and end tidal CO2 were monitored continuously, and CO2 was maintained at 3.5-4.2% by adjusting the respirator.
Recordings for determination of ocular dominance
The lid margins of the closed eye were separated, and both eyes were focused on a tangent screen at 57 in. by lenses of zero power and appropriate curvature. The nictitating membrane was withdrawn by a drop of 10% phenylephrine hydrochloride (Neosynephrine), and the pupils were dilated with a drop or two of 0.01% atropine. A tungsten electrode (Hubel 1957 Recordings for determination of the effect of MK-801 on activity
After determining the ocular dominance of a sample of cells, a computer-controlled bar of light was set up to stimulate the cell in the dominant eye with the preferred orientation, direction of movement, velocity, length, and width of the stimulus. The bar of light remained stationary on one side of the receptive field for 1 s and then swept across the receptive field, remained stationary for 1 s on the far side, swept back, remained stationary for 1 s more, and was then turned off. This procedure was repeated four times every minute; the average of these four responses constituted one group of records. Spikes were discriminated through a voltage window and monitored for amplitude and time course on a storage oscilloscope. The computer was also used to store spike discharge times and to construct a peristimulus time histogram (PSTH) on-line as the spikes came in. The first PSTH was displayed in red, and each subsequent PSTH was displayed in green, updated each minute, so that the effect of the injection of MK-801 could be monitored as it occurred. Spike discharge times together with details of the stimulation parameters were stored on hard disk for subsequent off-line analysis with custom-written ASYST programs (Asyst Software, Rochester, NY).
Histology
On completion of the physiological recordings, the animal was deeply anesthetized with 4% halothane and then perfused through the heart with 100 ml of Lactated Ringer, followed by 350-450 ml of 4% paraformaldehyde. The lateral gyrus was removed and allowed to sink in a 30% sucrose solution containing 4% paraformaldehyde. Frozen sections were cut at 60 µm and then stained with thionin (Nissl stain). Lesions were 50-100 µm in diameter. The electrode tracks were reconstructed, and the layer in which each cell was recorded was determined according to the layering criteria described by Kelly and Van Essen (1974) Analysis of data
For analysis of the effect of MK-801 on the activity of a cell, firing rates, expressed as spikes/s, were averaged over the entire response duration for one direction of stimulus presentation (typically 1-2 s). Visual responses were expressed as average firing rate while the stimulus was in the receptive field minus spontaneous activity. If the cell was unidirectional, the firing rate was measured while the stimulus was moving in the preferred direction. If the cell was bidirectional, the firing rate was considered to be the average of the firing rates in both directions.
Effect of MK-801 on dose response curves for NMDA or AMPA
Fourteen animals were recorded, aged 37-43 days of age. A cell was isolated, and the preferred parameters for stimulation were established. Visual response was measured, and then the responses to iontophoresis of NMDA or AMPA were measured. For iontophoresis, the cycle was NMDA on for 15 s, off for 57 s, AMPA on for 15 s, off for 57 s, and so on, varying the iontophoretic current to accumulate a series of firing rates between 0 and 50 Hz. In an ideal experiment, we recorded visual and iontophoretic responses for two or three cells, then injected MK-801, and then held the cell recording two or three visual responses and an iontophoretic response once an hour. Four hours after the first injection of MK-801, a second injection of MK-801 was given, and we continued to record for another 4-6 h. Because of the difficulty of holding a cell for 10 h, we did not always obtain this ideal result, in which case a new cell would be isolated and recorded with the same procedure. Visual responses, iontophoretic responses, and spontaneous activity were calculated off-line by our ASYST program and a straight line fitted to the linear portion of the dose-response curve by Slide Write (Advanced Graphics Software, Carlsbad, CA).
Effect of MK-801 on ocular dominance shifts
In the first series of experiments, we compared ocular dominance histograms from three animals treated with MK-801 and two animals treated with saline. All animals were deprived for a total of 40 h, 8 h/day over 5 days and then kept in the dark until recorded. Cells in the control animals were driven by the open eye more often than cells in the animals treated with MK-801 (Fig. 1). Weighted ocular dominances for the three animals treated with MK-801 were 0.58, 0.51, and 0.70 compared with weighted ocular dominances of 0.68 and 0.71 for the two control animals. In other words, treatment with MK-801 reduced the ocular dominance shift, but not greatly.
Effect of MK-801 on activity of single cells in the cortex
Thirteen cells were analyzed for the effect of MK-801 on their activity. The dose of MK-801 given was the average of the doses given during the rearing paradigm for animals treated with MK-801 during rearing. The dose given to control animals was the same as that given to treated littermates during rearing. Two cells were recorded in the first series of experiments, and 11 cells were recorded in the second. Eight were recorded from MK-801-treated animals, and five were recorded from control animals. Details of the age of the animal, MK-801 dose, and the layer of the cell recorded are given in Table 2.
Effect of MK-801 on responses of cells to NMDA and AMPA
We obtained results in 10 animals for the effect of MK-801 on the cortical responses to NMDA and AMPA as well as on the visual response. An example is shown in Fig. 5. The cell responded to movement in both directions for a bar of light moved at 4°/s. The visual response 4.5 h after the first injection of MK-801 and 30 min after the second was close to the response before injection of MK-801 (Fig. 5, top). AMPA and NMDA, both iontophoresed at 20 nA, gave substantial responses before injection of MK-801 (Fig. 5, left); 4.5 h later, after two injections of MK-801, the currents required were higher, but AMPA iontophoresed at 33 nA gave a substantial response, whereas NMDA iontophoresed at 35 nA gave very little response (Fig. 5, right).
MK-801 produced a significant decrease in the ocular dominance shift that normally occurs after MD. This occurred with doses that did not have a substantial effect on spontaneous activity or visually evoked activity of most cortical neurons. The decrease in the ocular dominance shift occurred in all layers and was most obvious in layers II, III, and IV.
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
). The clearest example is the effect of monocular deprivation (MD). After MD the cortex becomes effectively disconnected from the deprived eye. N-Methyl-D-aspartate (NMDA) receptors are believed to play an important role in this process. The prime evidence for this conclusion is that infusion of the NMDA antagonist D-2-amino-5-phosphonovaleric acid (APV) into the visual cortex reduces the ocular dominance shift (Bear et al. 1990; Kleinschmidt et al. 1987). A similar result was obtained with infusion of the NMDA channel blocker (+)-5-methyl-10,11-dihydro-5Hdibenzo [a, d] cyclohepten - 5, 10 - imine hydrogen maleate (MK-801), also directly into the visual cortex (Rauschecker et al. 1990).
) and infusion of TTX into the visual cortex prevents ocular dominance shifts from MD (Reiter et al. 1987). Compared with TTX, APV produces a less dramatic decrease in activity. Iontophoresis of APV reduces activity in the visual cortex, and this effect is greater in young animals (Tsumoto et al. 1987). APV is effective in all layers before 3 wk of age, but the effect becomes restricted primarily to layers II and III after 6 wk of age (Fox et al. 1989). Infusion of 50 mM APV into the visual cortex at 1 µl/h (the procedure used by Kleinschmidt et al. 1987) leads to a substantial depression of activity in all layers, even in adult animals (Miller et al. 1989).
recorded from cells in the cortex of their animals 2 days after starting infusion of 50 mM APV. They found that the percentage of visually driven cells in the area from which they obtained ocular dominance histograms was normal, although the response was depressed. They did not quantify the extent of the depression. Moreover, the animals tested for the effect of APV on activity in the visual cortex were different from those tested for the effect of APV on ocular dominance shifts.
). As a control for whether the MK-801 had a specific effect in visual cortex, we then observed the effect of MK-801 on dose-response curves plotted from iontophoresis of NMDA or -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA).
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
View this table:
TABLE 1.
Conditions for monocular deprivation
) or a carbon fiber microelectrode (Armstrong-James and Millar 1979) was inserted into the cortex for recordings from single cells. The left cortex, ipsilateral to the open eye and contralateral to the sutured eye, was chosen because there is a slight dominance in the cortex by the contralateral eye. Therefore, ocular dominance changes are more noticeable when the cortex ipsilateral to the open eye is recorded (Daw et al. 1992).
). If the cell responded to movement along one axis, but substantially less along the perpendicular axis, it was called bidirectional. If the cell responded to movement in one direction, but substantially less to the opposite direction, it was called unidirectional. The width of tuning for a moving bar was judged by moving the stimulus through the receptive field and repeating this with angles further and further away from the preferred direction of movement until the response was no longer audible. Finally, the responses in the two eyes were compared by using the preferred stimulus. Two observers independently assigned an ocular dominance according to the seven-point scale introduced by Hubel and Wiesel (1962).
.
where Ni is the number of cells in ocular dominance group i (Kasamatsu et al. 1981
).
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
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FIG. 1.
Ocular dominance histograms from 3 animals treated with MK-801 and deprived for 40 h compared with ocular dominance histograms from 2 animals injected with saline and deprived over the same period of time.
; Olson and Freeman 1980), and there was no difference between the older animals and younger ones that received the same treatment.
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FIG. 2.
Ocular dominance histograms from 4 animals treated with MK-801 and deprived for 64 h compared with ocular dominance histograms from 4 animals injected with saline and deprived over the same period of time.
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FIG. 3.
Ocular dominance histograms from the 2nd series of animals analyzed by layer. More than 50% of the cells were in group 7 in all layers in the control animals, and <20% of the cells were in group 7 in all layers in MK-801-treated animals.
). However, the angle over which the cell responded was not significantly different: 86 ± 24° for MK-801 animals compared with 88 ± 29° for controls. In the 13 cells where we had quantitative records, the firing rate in animals treated with MK-801 (9.3 ± 3.2 spikes/s, means ± SD) was not significantly different from the firing rate in control animals (6.3 ± 3.2 spikes/s): if anything, the firing rate in the treated animals was higher.
View this table:
TABLE 2.
Effect of MK-801 on activity of cells in animals tested for ocular dominance shifts
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FIG. 4.
A: cell for which injection of MK-801 had no effect. Record shows the visual response averaged over 16 trials spaced over 4 and 2 min before and 2 min after the time shown on the horizontal axis. MK-801 was injected at time 0. B: cell for which injection of MK-801 had no effect, but the response of the cell over time showed considerable variability. C: cell for which injection of MK-801 decreased the response to 25% over 20 min, with recovery to 60% after 60 min.
1 h. Consequently the decrease in these two cases could have been due to small shifts in the distance of the electrode from the cell, as a result of which amplitude of the action potential fell below the threshold of the window used to discriminate the action potential from noise.
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FIG. 5.
Visual response, response to iontophoresis of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and response to iontophoresis of N-methyl-D-aspartate (NMDA), measured in a layer II/III cell before injection of MK-801 and 30 min after the 2nd injection of MK-801.
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FIG. 6.
Dose-response curves for iontophoretic injection of NMDA and AMPA on a visual cortex cell before and after injection of MK-801. 
and - - -: data for response to AMPA with line fitted; + and 
: data for responses to NMDA and line fitted to them.
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FIG. 7.
A: slope of NMDA dose-response curve relative to slope of AMPA dose-response curve before and after 2 injections of MK-801 spaced 4 h apart. B: visual responses and spontaneous activity for cells recorded from the same animal over the same period of time.
View this table:
TABLE 3.
Effect of MK-801 on activity of cells in animals used for iontophoresis
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
). Bear et al. (1990) and Rauschecker et al. (1990) also found that the ocular dominance shift was not completely abolished by their injections of APV and MK-801 directly into the cortex. Of the many treatments that affect ocular dominance shifts (see Daw 1994 for a list), only complete abolition of activity in the cortex with TTX was proved to lead to a complete abolition of the ocular dominance shift (Reiter et al. 1986).
; Miller et al. 1989; Tsumoto et al. 1987). We agree with all of these authors that NMDA receptor blockers can decrease visual responses, but we found that the dose is critical. We found that higher doses of MK-801 (0.2 mg/kg) affected activity of visual cortex cells, but the doses used in our ocular dominance experiments (0.1-0.15 mg/kg) did not. Thus our conclusion is limited; there is a dose of MK-801 that affects ocular dominance shifts without affecting visual responses, but we would not expect this to occur with all doses.
found a substantial loss in selectivity for orientation and direction, recording cells in animals with APV infused into the visual cortex. We found a much smaller loss of selectivity. This may have been due to the age of the animals. Treatment in the animals used by Bear et al. started at 3-5 wk of age, compared with 30-39 days for our animals. The critical period for direction selectivity ends earlier than the critical period for ocular dominance changes (Berman and Daw 1977; Daw and Wyatt 1976), and so probably does the critical period for orientation changes (Chapman and Stryker 1993; Kim and Bonhoeffer 1993). Consequently interventions early in the critical period should affect orientation, direction, and ocular dominance, whereas interventions late in the critical period should affect primarily ocular dominance. Alternatively, the difference could have been due to the difference in drugs (APV vs. MK-801) and routes of administration.
also found a reduction in response quality in their animals infused with APV. Cells with a brisk and reliable response were given a high response quality, whereas cells with a sluggish response were given a low response quality. We did not assess response quality in the neurons recorded to construct the ocular dominance histograms because we were primarily concerned with getting as large a sample as possible. Our impression, however, was that cells from both MK-801-treated animals and control animals responded equally vigorously. In addition, we did have a quantitative measure of the visual response in those neurons where we assessed the effect of injection of MK-801 on the visual response; in those neurons there was little difference between control and treated animals. Thus we did not see a decline in response quality after treatment with MK-801. This also could be due to a difference in the age of the animals.
).
) and was implicated in ocular dominance plasticity (Singer and Rauschecker 1982). Another possibility is that MK-801 does affect NMDA receptors engaged by visual inputs but that the receptors are only blocked by MK-801 when the visual inputs cause particularly sustained or strong levels of depolarization. It is known that MK-801 blocks NMDA receptors in an activity-dependent manner (McDonald et al. 1981), so it is conceivable that, at a particular dose of MK-801, heightened levels of visual activity are blocked but normal visual processing is not.
). The visual response is affected primarily by depolarization, whereas plasticity could be affected by both depolarization and/or calcium entry. Indeed, some forms of long-term potentiation (LTP) depend on calcium entry but not activation of NMDA receptors, suggesting that calcium entry is the more crucial property (Komatsu 1991; see also Nicoll and Malenka 1995). Moreover, calcium can activate various second effector enzymes such as calcium/calmodulin-dependent protein kinase II and protein kinase C, which play a role in LTP (Malenka et al. 1989; Malinow et al. 1989) and may play a role in plasticity in the visual cortex. We suggest that our MK-801 treatment blocked calcium entry enough to affect plasticity, and the depolarization block was not enough to affect the response of the cells significantly.
). It is difficult to detect a change in activity of <5-10%. A relatively minor change in activity if this magnitude could nevertheless be accompanied by a large change in the amount of calcium entering the cell at the dendritic spine caused by the nonlinearities in the relationship between depolarization and intraspinal calcium concentration.
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ACKNOWLEDGEMENTS |
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We thank J. Peters for help during the first series of experiments.
This work was supported by National Institutes of Health Grants RO1 EY-00053 to N. W. Daw and RO1 EY-04050 to B. Gordon.
Present address: B. Gordon, Institute of Neuroscience, University of Oregon, Eugene, OR 97403; K. D. Fox, School of Molecular and Medical Bioscience, University of Wales, Cardiff CF1 3US, UK; S.N.M. Reid, Jules Stein Eye Institute, University of California, Los Angeles, CA 90095; D. Czepita, 1st Dept. Ophthalmology, Pomeranian Medical Academy, 70-111 Szczecin, Poland.
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FOOTNOTES |
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Address for reprint requests: N. W. Daw, Dept. of Ophthalmology and Visual Science, New Haven, CT 06520-8061.
Received 26 May 1998; accepted in final form 28 September 1998.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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