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Report
1 School of Health and Sport Sciences, Osaka University, Toyonaka, Osaka 560-0043, Japan; 2 Department of Ophthalmology and isual Science, Yale University School of Medicine, New Haven, Connecticut 06520
Submitted 30 March 2003; accepted in final form 20 August 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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; Wiesel and Hubel 1965). In general, monocular deprivation (MD) results in a loss of binocular response, and the ocular dominance (OD) distribution of neurons shifts to the open eye due to activity-dependent synaptic modification. That is, MD causes a retraction of connections following a decrease in synaptic efficacy for the deprived-eye-inputs and a reinforcement of connections following an increase in synaptic efficacy for the open-eye-inputs, resulting in a shift of the OD distribution toward the open eye (Antonini and Stryker 1993, 1996; Hubel et al. 1977).
Activity-dependent synaptic modification requires an activation of specific intracellular signaling cascades (Daw 1994, 2003; Lee et al. 2000). One particular protein kinase that is crucially involved in OD plasticity in the visual cortex is cAMP-dependent protein kinase (PKA). Blockade of the cAMP/PKA pathway by 8-chloroadenosine-3', 5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-Cl-cAMPS) or genetic deletion of the RII
subunit of PKA eliminates MD-induced OD plasticity (Beaver et al. 2001; Fischer et al. 2002). Consistent with these in vivo studies, long-term potentiation and depression in vitro are also abolished by PKA blockade (Liu et al. 2003). In addition, both basal and metabotropic glutamate receptor–stimulated cAMP levels in the visual cortex peak in parallel with the critical period for the physiological effects of MD (Reid et al. 1996). These studies suggest that activation of the cAMP/PKA pathway is critical for OD plasticity during the critical period in the cat visual cortex.
On the other hand, it is known that MD combined with cortical infusion of muscimol, a GABAA receptor agonist, leads to an OD shift toward the deprived eye (Hata and Stryker 1994; Reiter and Stryker 1988). This paradoxical shift is called a reverse OD shift and is suggested to occur due to a retraction of the thalamocortical afferents of the open eye (Hata et al. 1999). Here, fundamental but important questions about the intracellular mechanisms underlying these two forms of OD plasticity remain to be answered. First, which intracellular signaling mechanism mediates the reverse OD shift? Second, does the same molecular mechanism underlie these different forms of OD plasticity? In other words, can a single mechanism account for varying experience-dependent synaptic modifications? To answer to these questions, we examined whether PKA is involved in the reverse OD shift or not by concurrent infusion of a PKA inhibitor and muscimol into the visual cortex of monocularly deprived kittens.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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Details of the experimental methods used in this study have been described elsewhere (Beaver et al. 2001) and have been approved by the Yale Animal Care and Use Committee. Six kittens (42–44 days old) were stereotaxically implanted with osmotic minipumps (Alzet model 2001, Durect, Cupertino, CA). Animals were given preanesthetic doses of acepromazine (0.1 mg/kg, im), atropine (0.04 mg/kg, im), and dexamethasone (1 mg/kg, im) and anesthetized with ketamine (25 mg/kg, im) and xylazine (1.5 mg/kg, im), intubated, and mounted in a stereotaxic instrument. Anesthesia was maintained with 0.5–1.2% halothane. To check the depth of anesthesia and condition of animal, each animal was monitored with a thermometer, EKG, pulse oximeter, and CO2 monitor. A small craniotomy (about 1.5 mm diam) was made at P5, L2 overlying the left visual cortex. The tip of a 28 G cannula connected to an osmotic minipump containing a mixture of 20 mM Rp-8-Cl-cAMPS (BioLOG, Bremen, Germany) and 30 mM muscimol (Tocris) in 330 mM phosphate-buffered saline (PBS) was implanted into the craniotomy to a depth of 1.5–1.7 mm below the surface of the cortex. Animals were given an antibiotic (Baytril, 2.5 mg/kg, im) and an analgesic (Buprenex, 0.005 mg/kg, im) to relieve pain.
MD
MD began the day following pump implantation. The animal was anesthetized with halothane (1.5–2.0%) and given proparacaine HCl 0.5% ophthalmic solution, the lid margins of the right eye were trimmed, and the eyelids were sutured together using 4-0 silk, leaving a small aperture at the medial edge for drainage. A small bead of antibiotic ointment (Neomycin-Polymixin-Bacitracin, Bausch and Lomb Pharmaceuticals Inc., Tampa, FL) was placed between the eyelids before closing. In addition, a systemic antibiotic (Baytril, 2.5 mg/kg, im) and an analgesic (Buprinex, 0.005 mg/kg, im) were administered during postoperative recovery.
Electrophysiological recording
Following 5 days of MD (6 days of drug infusion), animals were prepared for extracellular physiological recording of single units. Animals were sedated with acepromazine (0.1 mg/kg, im) and given a preanesthetic dose of atropine (0.04 mg/kg, im) and dexamethasone (1 mg/kg, im). Anesthesia was induced with 4% halothane in a mixture of 67% nitrous oxide and 33% oxygen and maintained with 0.5–1.2% halothane thereafter. After a tracheotomy and insertion of a cannula into the femoral vein, 2% viscous lidocaine was placed into the ears, the animal was placed into a stereotaxic instrument, the skull was opened up over the lateral gyrus, and a small hole was made in the dura for insertion of the electrode. All wound margins were treated with lidocaine. Animals were paralyzed by intravenous infusion of pancuronium bromide (Baxter Healthcare, Deerfield, IL) at 0.6–1.5 mg/h. Heart rate and end tidal CO2 were monitored continuously, and CO2 was maintained at 3.5–4.3% by adjusting the respirator.
The basic procedure for the recording experiment is the same as in previous study (Reiter and Stryker 1988). After determination of the size of the area in left cortex in which discharges of cortical cells were blocked by muscimol, the cannula and pump were removed. Then neural activity of the right hemisphere was recorded to quantify the effect of MD there as a control. In the muscimol-infused hemisphere, unit recording was started 
24 h after removing the osmotic minipumup to allow recovery of neuronal activity from the inhibitory effect of the muscimol. Recording was resumed from a far site that was more than 4 mm (horizontal distance) from the infusion center and followed by recording from a near site (within 4 mm). Two or more electrolytic lesions (3.8 µA for 10 s) were made in each penetration to allow reconstruction of the penetrations. At the end of the recording experiment, the animal was deeply anesthetized with 4% halothane and perfused through the heart with PBS, followed by 4% paraformaldehyde in PBS. Frozen sections of the visual cortex were cut at 50 µm and stained with methylene blue-azure II. Then, the penetrations were reconstructed to check the distance of the recordings from the infusion site, and to determine the layer for the cells recorded (Kelly and Van Essen 1974).
Data analysis
Ocular dominance histograms were constructed, and weighted ocular dominance (WOD) scores (Kasamatsu et al. 1981) were calculated as follows WOD = (1/6G2 + 2/6G3 + 3/6G4 + 4/6G5 + 5/6G6 + G7)/N where Gi is the number of cells in ocular dominance group i (i = 1–7; 1, deprived eye only; 7, open eye only) and N is the total number of cells. In this study, according to this scheme, a WOD score of 1 means that all cells responded only to the open eye, while a WOD score of 0 means that all cells responded only to the deprived eye. Values for these parameters are given as means ± SD, and significance for the various comparisons were tested with Student's t-test or a paired t-test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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5.5 mm from the cannula, because within this region, we could record neuronal activity only from geniculocortical afferents before the removal of the minipump.
The effect of 5 days of MD was assessed by recording from single neurons and determining the relative strength of the two eye's inputs according to the Hubel and Wiesel seven-category-scheme (Hubel and Wiesel 1962). Figure 1 shows OD histograms of the group data obtained from kittens treated with muscimol plus PKA antagnoist, Rp-8-Cl-cAMPS (top, n = 4) and muscimol only (bottom, n = 2). In the muscimol-treated visual cortex, the MD caused an OD shift toward the deprived eye (categories 1–3), which is called a "reverse OD shift" (bottom left; WOD score = 0.31 ± 0.02), and the PKA inhibitor did not prevent it (top left; WOD score = 0.28 ± 0.1). The recording tracks of all penetrations and distances from the cannula were confirmed by histological reconstruction. All units categorized as "near pump" were recorded within the area 2–4 mm from the pump cannula where the PKA inhibitor blocked the effect of MD on normal OD shift in our previous studies (Beaver et al. 2001, 2002). On the other hand, in the right (control) hemisphere, a clear OD shift to the open eye (categories 5–7) was observed in both PKA antagonist-treated (top right; WOD score = 0.87 ± 0.05) and -untreated (bottom right; WOD score = 0.89 ± 0.03) animals, demonstrating that the MD was successful in both treatment groups.
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To quantify the degree of the OD shift, we compared the WOD scores of varying experimental conditions with data from previous studies (Beaver et al. 2002; Hata and Stryker 1994; Reiter and Stryker 1988). Figure 2 illustrates WOD scores under varying conditions, and the shaded region (0.44 ± 0.06) indicates the WOD range that was calculated from previous results from 37 normal animals (10 days old–adult). A value larger than the shaded region means that the OD was shifted in favor of the open eye and a smaller value that the OD shifted toward the deprived eye. The WOD scores from the combination of MD and muscimol infusion were 0.28 ± 0.10 and 0.31 ± 0.02 in the presence and absence of PKA antagonist, respectively, and there was no significant difference between them. Those values were significantly smaller than that (0.44 ± 0.06) of normal animals (P < 0.01). These results were comparable to previous studies on the reverse OD shift (Reiter and Stryker 1988; WOD score = 0.32; Hata and Stryker 1994; WOD score = 0.32). Thus the PKA antagonist did not block the induction of reverse OD shift at all.
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Since the reverse OD shift accompanies the retraction of the thalamocortical afferents, there might be a laminar difference in the extent of OD shifts. Therefore OD histograms were constructed for individual layers (Fig. 3). Also, a WOD score was calculated for each lamina separately for each experimental condition to quantify the laminar difference (Fig. 4). In this analysis, cortical layers were classified into layers II/III (supragranular layer), IV (granular layer), and V/VI (infragranular layer) based on Otsuka and Hassler (1962). The laminar analysis demonstrated that the reverse OD shift was most prominent in layer IV in kittens treated with MD + muscimol + PKA and those with MD + muscimol. In normal (control) animals, there was no laminar difference in WOD score (0.43–0.46, P = 0.68). In contrast, MD + muscimol-treated kittens regardless of the presence or absence of the PKA antagonist showed a laminar difference with the lowest WOD score in layer IV. Statistical analysis (paired t-test) was applied to the results with the PKA antagonist but not to those without the PKA antagonist because of the small sample size, and a significant difference was observed between layer IV and layers II/III (P < 0.05). Thus a strong reverse OD shift occurred in the thalamocortical input layer, and weakly or did not in layers of subsequent cortical stages. In contrast, normal OD shift tended to be weakest in layer IV among cortical layers (Fig. 4).
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DISCUSSION |
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; WOD score = 0.32; Hata and Stryker 1994; WOD score = 0.32), 2) the most prominent reverse shift was observed in layer IV compared with other layers, and 3) the PKA antagonist, Rp-8-Cl-cAMPS, influenced neither induction of the reverse OD shift nor its laminar difference.
Inhibition of PKA blocks (4-wk-old kittens of Beaver et al. 2001) or at least severely reduces (6-wk-old kittens of Beaver et al. 2002) MD-induced OD shifts toward the open eye in active cortex but does not have a significant effect on the OD shifts toward the deprived eye in inactive, muscimol-treated, cortex. In this study, there is a possibility that the PKA pathway, particularly at postsynaptic cortical cells, has been blocked due to inhibition by muscimol rather than a direct inactivation of PKA by the PKA inhibitor. Since the activation of PKA depends on neural activity, the inhibition of cells by muscimol could suppress the PKA signaling pathway. In the previous study, we reported that the orientation selectivity was reduced by MD in combination with PKA inhibitors (Beaver et al. 2002). Therefore we checked the orientation selectivity of cells recorded in this study and found that there was no significant difference in the proportion of orientation-selective cells between the cell groups recorded from near the pump containing muscimol + PKA inhibitor (78.3 ± 22.9%; n = 4 animals; n = 89 cells) and the contralateral hemisphere (67.7 ± 18.8%; n = 4 animals; n = 102 cells; paired t-test, P = 0.96). The lack of effect of PKA inhibitor in reducing the orientation selectivity suggests that the PKA inhibitor might not be effective in the muscimol-treated cortex. However, we interpreted this result as that cortical neurons require the postsynaptic activity for the change of orientation tuning by blocking PKA activity, and PKA blockade would not affect orientation selectivity in muscimol-treated animals because the cortical cells were silenced. This point remains to be clarified.
However, this does not contradict our conclusion that the reverse OD shift does not require PKA, because even if activation of GABAA receptors with muscimol suppressed the intracellular PKA pathway, the reverse OD shift still occurred. Alternatively, if PKA was active despite the presence of muscimol (as would be the case for the presynaptic PKA at thalamocortical terminals), the reverse OD shift still occurred despite the presence of the PKA inhibitor. Either interpretation supports our conclusion that neither postsynaptic PKA in cortical neurons nor presynaptic PKA in afferent inputs is involved in the reverse OD shift. There is another possibility that inactivity of PKA in the muscimol-treated cortex plays a permissive role for the reverse OD shift. However, since the blockade of PKA did block the normal OD shift but did not induce the reverse OD shift (Beaver et al. 2001, 2002), the inactivity of PKA by itself is not sufficient for the permission of the reverse OD shift.
These results suggest that the molecular mechanisms underlying these two forms of OD plasticity are different from each other. This is the first evidence that a single molecular mechanism cannot account for varying activity-dependent OD plasticity in vivo.
The primary morphological mechanism of the reverse OD shift is suggested to be a specific retraction of synapses of active thalamic afferents serving inputs from the open eye due to uncorrelated activity between cortical neurons and afferents (Hata et al. 1999). On the other hand, terminals from the deprived eye do not change much over the first 2 wk of MD with muscimol (Hata et al. 1999). Therefore our results suggest that PKA is associated with the activity-dependent competition in the normal OD shift but not with the specific elimination of synapses with uncorrelated pre- and postsynaptic activity.
The extent of reverse OD shift was most prominent in layer IV. During cortical inactivation with muscimol, cells except for input layer IV do not receive significant visual inputs. That is, the anti-correlation of the pre- and postsynaptic activity occurs primarily at thalamocortical synapses in layer IV but not at corticocortical synapses. Therefore the OD shift toward the deprived eye observed in supra- and infragranular layers, if any, seems to reflect the secondary reduction of open eye inputs due to the reverse OD shift in the layer IV.
In contrast, between 4 and 6 wk of age, the ocular dominance in all layers can be completely shifted by a few days of classical MD (Hubel and Wiesel 1970; Movshon and Dursteller 1977; Olson and Freeman 1975). Also, the OD shift occurs more rapidly in extragranular layers than in layer IV (Trachtenberg et al. 2000), and the susceptibility to the MD lasts longer in the extragranular layers than in layer IV (Daw et al. 1992). This discrepancy of the laminar difference between two types of plasticity can be explained by the distribution of active synapses in the visual cortex. That is, for the classical MD, virtually all the synapses including the geniculocortical and corticocortical ones are active. There must be a substantial difference in the magnitude of activity between non–deprived-eye–related and deprived-dye–related synapses in all layers. In extragranular layers, the recurrent excitatory network of exuberant axon collaterals may accentuate the imbalance of activity between more active and less active synapses. These are possible mechanisms for the laminar distribution of the normal OD shift.
In the case of the reverse OD shift, however, only presynaptic terminals of thalamocortical afferents localized in layer IV are active and corticocortical synapses in all layers within the muscimol-infused area are inactive, which will confine the primary reverse OD shift to layer IV.
It has been thought that the experience-dependent synaptic modification observed in in vivo and in vitro experiments have relevance to each other (Daw 1994). In in vitro studies, longterm depression (LTD) in the hippocampus and neocortex can be classified into two categories according to induction procedures: hetero- and homosynaptic LTD (Artola et al. 1990; Stanton and Sejnowski 1989). Heterosynaptic LTD can be induced at synapses when its neighboring input pathway is activated and homosynaptic LTD at synapses when its activation does not accompany postsynaptic activity. The normal OD shift in layer IV seems to involve both long-term potentiation (LTP) of active synapses serving open eye inputs and heterosynaptic LTD of inactive synapses serving deprived eye inputs (Tsumoto and Suda 1979), and it is possible that PKA mediates both forms of synaptic plasticity because the PKA inhibitor blocked the normal OD shift (Beaver et al. 2001). On the other hand, the reverse OD shift in layer IV seems to be due to homosynaptic LTD of anti-correlated activity of pre- and postsynaptic neurons, and PKA is not involved in this form of plasticity. Recent studies on mice with targeted knockout for either glutamic acid decarboxylase 65-kD gene (GAD65-KO mice) or type 2 metabotropic glutamate receptor gene (mGluR2-KO mice) demonstrated that induction of normal OD plasticity in vivo by MD is dissociated from that of homosynaptic LTD induced in slice preparation (Hensch et al. 1998; Renger et al. 2002). These results are consistent with our findings that homosynaptic LTD is not associated with the normal OD shift but is associated with the reverse OD shift.
There is an intriguing report that MD combined with cortical infusion of the antagonist of N-methyl-D-aspartate (NMDA) receptor, D,L-2-amino-5-phosphonovalerate (APV), caused a reverse OD shift only in a region near the infusion site (Bear et al. 1990). It has been reported that presynaptic inputs which activate postsynaptic cells insufficiently to trigger LTP rather produces LTD (Cormier et al. 2001). Since APV counteracts the opening of NMDA receptor–gated Ca2+ channels, an activation of postsynaptic cells in the APV infused region by open-eye related inputs could be much less than that in the intact cortex, which results in the homosynaptic LTD, i.e., the reverse OD shift.
In general, the various forms of OD plasticity have been explained by the covariance rule of pre- and postsynaptic activity (Cruikshank and Weinberger 1996). Although this rule is useful to pigeonhole the phenomena including MD-induced normal and reverse OD shifts, the intracellular signaling mechanisms underlying them are different from each other and more complex than ever has been thought. Therefore systematic experiments are required to clarify the precise mechanism that translates relationships between pre- and postsynaptic activity to plastic changes of synaptic efficacy.
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DISCLOSURES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. Shimegi, School of Health and Sport Sciences, Osaka Univ., Machikaneyama, Toyonaka, Osaka 560-0043, Japan (e-mail: shimegi{at}vision.hss.osaka-u.ac.jp).
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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