Cerebral Cortex Advance Access originally published online on January 4, 2006
Cerebral Cortex 2006 16(12):1750-1758; doi:10.1093/cercor/bhj110
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Strabismic Suppression Is Mediated by Inhibitory Interactions in the Primary Visual Cortex
1 Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK, 2 Department of Neurophysiology, Ruhr-University Bochum, D-44780 Bochum, Germany
Address correspondence to Frank Sengpiel, Cardiff School of Biosciences, Museum Avenue, Cardiff CF10 3US, UK. Email: SengpielF{at}cf.ac.uk.
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Abstract |
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Most strabismic observers do not suffer from double vision because of suppression from conscious perception of 1 of the 2 eyes' conflicting views. Direct evidence for the site and neural substrate of strabismic suppression has not been available so far, although psychophysical data suggest a cortical origin. On the other hand, cross-orientation suppression among conflicting stimuli presented monocularly has recently been shown to have a strong thalamic component. Here we present evidence, using both visual stimulation and pharmacological techniques, that strabismic suppression occurs in the primary visual cortex and involves
-amino butyric acid (GABA)–mediated inhibition. We show that its dependency on the drift rate of the suppressing stimulus is consistent with a cortical origin; unlike monocular cross-orientation suppression, it cannot be evoked by very fast–moving stimuli. Furthermore, strabismic suppression is greatly reduced when GABAergic inhibition is locally blocked by the GABAA antagonist bicuculline.
Key Words: GABA • inhibition • orientation • strabismus • striate cortex
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Introduction |
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Strabismus or squint, the misalignment of the visual axes of the 2 eyes, is a common visual disorder in humans, which usually develops at an early age (for reviews, see Duke-Elder and Wybar 1973
; von Noorden 1990). Despite the fact that the images of each feature in the visual scene fall on geometrically noncorresponding points in the 2 retinae, most subjects do not suffer from diplopia or double vision. In some cases, this can be attributed to the phenomenon of anomalous retinal correspondence, where functional correspondence is shifted to match the angle of squint. More commonly, diplopia is prevented through suppression from conscious perception of 1 of the 2 eyes' conflicting views. In case of subjects with unilateral fixation, the image seen by the constantly deviating eye is suppressed permanently, whereas in subjects with alternating fixation, suppression also switches from eye to eye, with the image received by the nonfixating eye being suppressed. With convergent squint (esotropia), unilateral fixation is much more common than with divergent squint (exotropia), as is amblyopia, a loss of visual acuity that persists after correction of refractive errors, in the absence of any ocular pathology. Strabismic suppression is traditionally considered to be the cause of strabismic amblyopia (Travers 1938; von Noorden 1990; Sengpiel and Blakemore 1996), a hypothesis that is supported by the findings that the strength of suppression and the severity of amblyopia are correlated (Sireteanu and Fronius 1981). Moreover, suppression is stronger in the nasal hemiretina of amblyopic esotropes than in the temporal hemiretina (Sireteanu and Fronius 1981), as one would expect because an object present in the fovea of the fixating eye will be imaged in the nasal hemiretina of the deviating eye. Also, in subjects with alternating fixation, the suppression of the deviated eye is strongest in a region corresponding to the fovea of the fixating eye but reduced or absent in the periphery (Sireteanu 1982).
Until recently, little direct evidence was available regarding the site and nature of the suppressive mechanism, which results in virtual blanking of vision in the nonfixating eye, although psychophysical evidence pointed to a cortical origin (Blake and Lehmkuhle 1976; Hess 1991). Most neurophysiological studies of strabismic cats or monkeys had employed monocular stimulation through either eye in order to characterize receptive field properties of neurons, in particular in the primary visual cortex (V1). These studies all agree in that strabismus, whether convergent or divergent, leads to a marked reduction in the proportion of neurons in V1 that are excitable through either eye (e.g., Hubel and Wiesel 1965; Blakemore 1976; Crawford and von Noorden 1979; Singer and others 1980; Van Sluyters and Levitt 1980; Mower and others 1982; Crawford and others 1984; Sengpiel and others 1994). In monkeys, this loss of binocularity is accompanied by poor binocular summation performance and an inability to see random dot stereograms (Crawford and others 1983). These deficits are very similar to defects of binocular summation and stereopsis in strabismic humans (Lema and Blake 1977; Levi and others 1979).
Otherwise, physiological deficits in V1 are rather subtle, as far as monocular response properties are concerned. Neuronal orientation tuning as well as contrast sensitivity are largely normal in both cats and monkeys (Sengpiel and others 1994; Kiorpes and others 1998), whereas spatial resolution has been found to be reduced in some amblyopic cats and monkeys, but not to an extent as to fully explain the behavioral deficit (Chino and others 1983; Crewther DP and Crewther SG 1990; Kiorpes and others 1998).
Using true binocular stimulation, we previously found that surgically induced strabismus in cats virtually abolishes the disparity-specific binocular interactions that are such a distinctive feature of normal neurons in area 17 (Sengpiel and others 1994). Instead, we observed pronounced, nonspecific interocular suppression in the majority of cells: stimulation of the nondominant eye with a grating of any orientation depressed the response to an optimal grating being presented to the dominant eye (Sengpiel and Blakemore 1994; Sengpiel and others 1994). A similar result was obtained in V1 of monkeys with surgically (Sengpiel and Blakemore 1996) or optically induced squint (Smith and others 1997).
We have speculated that interocular suppression in strabismic subjects is an abnormal form of the sort of inhibitory binocular interaction that may underlie binocular rivalry experienced by normal subjects (Sengpiel and Blakemore 1994; Sengpiel and others 1994). We have further suggested that the site of interocular suppression is V1, with suppression being mediated by inhibitory horizontal connections between opposite-eye columns (Sengpiel and others 1994). However, no direct evidence has been available so far. On the contrary, a recent paper on the apparently similar phenomenon of cross-orientation suppression (elicited by pairs of gratings superimposed in 1 eye) suggested that it is more likely to be subcortical in origin (Freeman and others 2002).
Here we present evidence, using both visual stimulation and pharmacological techniques, that strabismic suppression occurs in area 17 and involves -amino butyric acidergic (GABAergic) inhibition.
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Materials and Methods |
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Data were obtained from 5 young cats (age, 2.5–12 months) bred in a closed laboratory colony. All experiments were carried out in accordance with UK Home Office regulations on animal experimentation (Animals [Scientific Procedures] Act 1986) and the German Animal Protection Law and the European Communities Council Directive 86/609/EEC. Efforts were made to minimize animal suffering and to reduce the number of subjects used.
Strabismus was induced at around 3 weeks of age (between postnatal days 19 and 22). Animals were anesthetized with an intramuscular injection of ketamine (20–40 mg/kg) and xylazine (2–4 mg/kg), and a topical anesthetic (amethocaine) was instilled in the conjunctival sac. In 2 cats, exotropia was induced by myotomy; through a small incision in the conjunctiva, the medial rectus muscle was secured with a muscle hook and detached from the globe. In 3 other animals, esotropia was induced by myotomy of the lateral rectus in 1 eye. Recovery was rapid, with no evidence of pain or distress. The animals were checked frequently for the first few days after surgery, to be sure that no infection occurred and that the lids of the operated eye remained open, and thereafter to ensure that the operated eye did not return to its normal position.
Surgery
Details of animal preparation have been described elsewhere (Sengpiel, Blakemore, and Harrad 1995). Briefly, anesthesia was induced with an intramuscular injection of ketamine (20–40 mg/kg) and xylazine (2–4 mg/kg). Following tracheal cannulation, animals were artificially ventilated and anesthetized with a mixture of N2O (55–70%), O2 (30–45%), and either halothane (2 animals) or isoflurane (3 animals). Respiration rate and inspiratory pressure were adjusted to maintain end-tidal CO2 at 3.5–4.5%. During recording, the animal was paralyzed with a continuous intravenous infusion of gallamine triethiodide (10 mg/kg/h) or alcuronium chloride (0.06 mg/kg/h) in glucose saline. Electrocardiogram and electroencephalogram were constantly recorded, and the anesthetic level was adjusted as necessary to guarantee stable anesthesia. Body temperature was monitored and kept near 38 °C. The pupils were dilated with atropine hydrochloride, and the lids and nictitating membranes retracted with phenylephrine. Animals were refracted, and contact lenses with artificial pupils were fitted to correct focus for a viewing distance of 50 cm. A trepanation was made above area 17 of one or both the cortical hemispheres, and a small hole was made in the dura. The area was covered with agar to protect the surface of the cortex and to minimize pulsations.
Electrophysiology and Visual Stimulation
Animals viewed, via front-silvered mirrors, a 21-inch monitor positioned at a distance of 50 cm on which stimuli were presented independently to the 2 eyes on the left and right half. Drifting, sinusoidally modulated gratings of high contrast (mean luminance, 38 cd/m2) were generated by a visual stimulus generator (VSG Series Three, Cambridge Research Systems, Rochester, UK). External stimulus control, data acquisition, and analysis were performed using "Brainware" software (Tucker-Davis Technologies, Alachua, FL). For analog-to-digital conversion, either a CED1401 interface (Cambridge Electronic Design, Rochester, UK) or a System II (Tucker-Davis Technologies) was used.
Triple-barreled borosilicate glass micropipettes (World Precision Instruments, Stevenage, UK) were used for recording and drug application. One barrel was used for single-cell recordings, and the others were filled with the GABAA antagonist (–)-bicuculline methiodide (5 mM, pH 5.5; Sigma, Poole, UK). Pipettes were advanced into area 17, using a hydraulic microdrive (Narishige International Ltd, London, UK). Iontophoresis was controlled by 2 IP-2 units in a Neurophore BH-2 system (Digitimer, Welwyn Garden City, UK). A retaining current of –5 to –10 nA was used depending on the level of barrel resistance (measured in saline and at the cortical surface; only barrels with 80–200 M
resistance were used). An initial ejection current of +10 nA was reduced to +3 nA to maintain a stable response to an optimally oriented grating as well as to a blank screen (see Results).
We recorded extracellularly from neurons throughout the depth of area 17, in the region representing the center of the visual field; single units were discriminated by their spike shapes. For each neuron, we first obtained monocular tuning curves for orientation/direction of movement and spatial frequency. Left- and right-eye responses to drifting gratings of 16 different directions in 22.5° steps were averaged over 5 trials of 1.5-s duration, and the preferred orientation was determined from these curves. Spatial frequency tuning curves were obtained for both eyes with gratings of optimal orientation and 12 spatial frequencies ranging from 0.1 to 4.52 cycles/degree in 1/2 octave steps.
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Results |
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Orientation Tuning of Binocular Interactions
Orientation tuning of binocular interactions was assessed by stimulating the dominant eye with a drifting grating at the cell's preferred orientation and spatial frequency and presenting to the other eye drifting gratings of the same spatial frequency but varying in orientation. The 2 gratings always drifted at the same temporal frequency of 2 Hz. Each epoch of binocular stimulation lasted 1.5 s, and responses from at least 8 trials were averaged. We recorded from 88 single neurons, of which 35 (44%) exhibited clear interocular suppression.
For 25 neurons, binocular responses were depressed below the level of the response to dominant-eye stimulation alone (measured with a blank screen shown to the nondominant eye) irrespective of the orientation of the stimulus shown to the nondominant eye (see Sengpiel and others 1994); a typical example is shown in Figure 1B. Notably, all cells exhibited normal orientation tuning of responses to monocularly presented gratings (e.g., Fig. 1A). There was no correlation between the strength of suppression and the degree of binocularity among these cells (r = 0.13). Moreover, orientation-independent suppression was observed equally among cells dominated by the deviated eye (12 neurons) and those dominated by the normal eye (13 cells). In 10 cells, interocular suppression was limited to large interocular orientation differences (of 30° or more). In these cells, which typically responded well through both eyes when stimulated monocularly (see Fig. 2A), either binocular interactions were virtually absent when the stimuli in the 2 eyes were of the same (optimal) orientation (Fig. 2B) or weak facilitation was observed.
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Dependence of Suppression on Intracortical Inhibition
In order to test the hypothesis that strabismic suppression is caused by intracortical inhibition operating among neurons of different eye dominance, we measured interocular suppression before and after blocking intracortical inhibition with the GABAA antagonist bicuculline.
For all cells with orientation-independent suppression, we determined the strength of interocular suppression as the mean of response reductions across the range of orientation differences tested (from –90° to 90°). For cells that showed some iso-orientation facilitation, we calculated the strength of interocular suppression as the mean of response reductions at interocular orientation differences of ±45° and ±90° (orthogonal suppression).
Binocular interaction functions for a typical neuron exhibiting orientation-independent suppression are shown in Figure 1B. For this monocular cell dominated by the normal eye, the binocular response was, on average, just 68.2% of the response elicited through the dominant (nondeviated) eye, that is, suppression was at 31.8%.
We then antagonized intracortical inhibition by bicuculline iontophoresis, the level of which was carefully controlled such that spontaneous activity (measured in response to a blank screen) did not switch to bursting and did not increase by more than 100% or above 10 spikes/s, and orientation selectivity of responses was maintained, even though orientation tuning typically widened (Sillito 1979). In particular, nonspecific burst firing was kept to a minimum. The orientation tuning of monocular responses was reassessed at 5-min intervals. Only after response levels had stabilized did we retest binocular interactions. For the cell shown in Figure 1, in the presence of bicuculline, the previously pronounced interocular suppression was reduced from 31.8% to 7.8% of the monocular control response.
The cell depicted in Figure 2 was binocular, with the deviated-eye response slightly stronger (Fig. 2A). It showed pronounced cross-orientation but very little iso-orientation suppression under dichoptic stimulation (Fig. 2B). After bicuculline iontophoresis, binocular responses were close to or above the monocular control response for all orientation combinations. Instead of the previously observed cross-orientation suppression, there was even some elevation above the monocular level at large interocular orientation differences (Fig. 2B).
Among the 35 neurons tested, all but 1 displayed a reduction in the relative strength of interocular suppression after application of bicuculline. A scatter plot of data from all cells is shown in Figure 3. On average, interocular suppression was 29.3 ± 2.2% (mean ± standard error of the mean) prior to application of bicuculline and 12.0 ± 2.7% during application of bicuculline. Suppression under these 2 conditions differed significantly (P < 10–6, paired t-test). For 12 neurons, we succeeded in measuring recovery from the effects of bicuculline 20–40 min after switching back from ejection to retention current. For this subset, interocular suppression of 30.6 ± 2.4% was obtained, which was indistinguishable from the value before iontophoresis (P > 0.7, paired t-test). This result demonstrates that interocular suppression was selectively reduced by antagonizing intracortical inhibition.
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Phase Dependence of Binocular Interactions
For 54 cells, the dependence of binocular interaction on the relative spatial phase of dichoptically presented gratings was tested both before (control) and during iontophoresis of bicuculline. As reported before (Sengpiel and others 1994), the relative phase offset between 2 optimally oriented gratings had little modulatory influence on neuronal responses. Figure 4A displays mean population responses, with individual response curves having been shifted to peak at a nominal phase offset of 270°. The responses at the best phase were just 1.25 times as strong as at the worst phase. The only discernible effect of bicuculline was an overall response elevation (ratio of best-phase and worst-phase responses, 1.21). For comparison, population responses of 28 area 17 neurons recorded from 2 age-matched normal control animals are illustrated in Figure 4B. These were strongly phase modulated, the responses at the best phase being 2.15 times as strong as at the worst phase. Bicuculline iontophoresis markedly reduced this modulation to a factor of 1.54 (Fig. 4B). Interestingly, and in contrast to the cells recorded from strabismic animals (Fig. 4A), bicuculline iontophoresis did not increase activity at the best phase but purely decreased inhibition at the worst phase.
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Dependence of Suppression on Temporal Frequency (Drift Rates)
A recent paper showed that cross-orientation suppression (Morrone and others 1982) caused by orthogonal pairs of superimposed gratings presented to 1 eye can be elicited with gratings drifting too fast to evoke an excitatory response from cortical neurons (Freeman and others 2002). Cross-orientation suppression is therefore unlikely to derive from a pool of cortical cells providing an inhibitory input to the recorded neuron. Instead, the authors suggested that it may be caused by depression of thalamocortical synapses. In contrast, the dependency of interocular suppression elicited by dichoptically presented orthogonal gratings on the drift rate of the suppressing stimulus is consistent with a cortical origin; it cannot be evoked by very fast–moving stimuli (Sengpiel and Vorobyov 2005). Here we employed the same stimulus paradigm in order to test whether or not the temporal frequency tuning of strabismic suppression matches the excitatory population response of the cortical neurons from which it is hypothesized to derive.
For each cell, we determined monocular tuning curves for temporal frequency through both eyes with gratings of 100% contrast drifting at 2, 4, 8, 16, or 32 Hz (Fig. 5A); because of the breakdown of binocularity in strabismus, in many cases a clear response was seen only for the dominant eye. Most cells responded maximally at 2 or 4 Hz, and the response was close to spontaneous firing at drift rates above 8 Hz. We measured strabismic suppression across the same range of temporal frequencies. Cells were stimulated through the dominant eye with a grating of optimal orientation and spatial frequency and at a fixed drift rate of 2 Hz. Interocular suppression was assessed by presenting to the other eye orthogonal mask gratings at 100% contrast and 2-, 4-, 8-, 16-, or 32-Hz drift rate (Fig. 5B, filled diamonds). For comparison, monocular cross-orientation suppression was also assessed, by superimposing in the same (the dominant) eye orthogonal gratings at 50% contrast; again, the drift rate of the mask grating was 2, 4, 8, 16, or 32 Hz (Fig. 5B, open squares).
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Temporal frequency tuning of strabismic, or interocular, suppression was recorded for 21 neurons and monocular cross-orientation suppression for 11 of these. All the cells included in this study were orientation selective, and the responses to the orthogonal-to-optimum mask grating alone (either in the dominant or in the nondominant eye) were not significantly different from the response to a blank screen for any of them. Responses for 1 typical neuron, which responded slightly more strongly through the deviated than through the normal eye, are displayed in Figure 5. In the control condition (Fig. 5B), interocular suppression was observed for the same range of drift rates, 2–8 Hz, that elicited an excitatory dominant-eye response (Fig. 5A). By comparison, pronounced monocular cross-orientation suppression was present up to 16 Hz. Following bicuculline iontophoresis, interocular suppression was largely abolished (Fig. 5D), whereas monocular suppression was clearly reduced at low drift rates (2 and 4 Hz) but not at high drift rates (8 and 16 Hz).
For the population of cells studied under this paradigm, a similar picture emerged (Fig. 6). The drift tuning curves of all cells were first normalized to the monocular, dominant-eye response at 2 Hz (Fig. 6A). We also normalized the responses under both suppression paradigms to that same dominant-eye response at a 2-Hz drift rate and then averaged responses across the population of cells (Fig. 6B). Significant cross-orientation suppression (P < 0.01, Newman–Keuls test for multiple comparisons) was observed at drift rates up to 16 Hz, with maximal suppression (51%) at 4 Hz. Interocular suppression also peaked at 4 Hz (28%), was significant up to 8 Hz (P < 0.01, Newman–Keuls test) and was absent at 16 and 32 Hz. Inspection of the response versus drift rate curves reveals that the population tuning of interocular suppression is well matched to the tuning of the dominant-eye responses, whereas monocular suppression extends to higher temporal frequencies (see Fig. 6B).
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Bicuculline iontophoresis did not affect monocular drift tuning qualitatively (Fig. 6C) but caused a reduction in strabismic suppression across the effective range of drift rates from 2 to 8 Hz (Fig. 6D). As in the control condition (Fig. 6B), suppression peaked at 4 Hz but was reduced in strength to 15%. Interestingly, the population response to the monocular cross-orientation mask was affected by bicuculline only at the lower drift rates of 2 and 4 Hz, where suppression was reduced from 43% and 51% to 33% and 32%, respectively. In contrast, at higher rates, bicuculline made little difference to cross-orientation suppression (cf., Fig. 6A,B): at 8 Hz it decreased slightly from 49% to 44% and at 16 Hz it increased slightly from 29% to 36%. Therefore, GABAergic inhibition may contribute to cross-orientation suppression at low temporal frequencies, whereas at higher temporal frequencies, a different mechanism is likely to act, such as depression of geniculocortical transmission (Freeman and others 2002
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Discussion |
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We have shown that strabismic suppression in cat area 17 elicited by dichoptic grating pairs is characterized by 1) a dependency on GABAergic cortical inhibition and 2) a similar dependency on temporal frequency as found for the population response to monocular stimulation with single gratings. In contrast, cross-orientation suppression by monocularly presented grating pairs was observed at higher temporal frequencies and was less dependent on GABAergic inhibition. Together, these results strongly suggest that strabismic suppression is primarily a cortical phenomenon mediated by inhibitory circuitry within area 17. The only possible alternative explanation of our findings could be an increase in neuronal excitability caused by bicuculline, but the stimulus specificity of the pharmacological effects makes this very unlikely. Moreover, previous studies on both normal (Sillito and others 1980
) and monocularly deprived cats (Sillito and others 1981) have demonstrated the existence of inhibitory inputs from the nondominant eye onto apparently monocular neurons in area 17. Such neurons form the majority of cells in area 17 of strabismic cats (see also Sengpiel and others 1994). Site and Nature of Interocular Suppression
Our findings are in agreement with similar results for interocular suppression in normal cat area 17 (Sengpiel and Vorobyov 2005) and argue in favor of our earlier hypothesis that strabismic suppression is an abnormal form of interocular suppression in a situation where there is permanent rivalry between 2 conflicting retinal images (Sengpiel and others 1994). By contrast, cross-orientation suppression caused by monocular superimposed gratings likely has a predominantly subcortical substrate (Freeman and others 2002). The finding of cross-orientation suppression at drift rates of the mask beyond the response limits of almost all cortical neurons and immunity of suppression against adaptation to the suppressor suggests that it originates in the lateral geniculate nucleus (LGN) where cells commonly respond to grating drift rates in excess of 20 Hz (Saul and Humphrey 1990; Freeman and others 2002), whereas V1 neurons rarely respond beyond 15 Hz (Movshon and others 1978; DeAngelis and others 1993). Moreover, adaptation causes at most a modest reduction of LGN responses (Shou and others 1996; Sanchez-Vives and others 2000) while significantly decreasing the responses of almost all cortical neurons (Maffei and others 1973; Albrecht and others 1984; Ohzawa and others 1985). Taken together, interocular forms of suppression, in either normal or strabismic cats, appear to have at least in part a different neural substrate than monocular forms. Given that interocular suppression is considerably weaker than monocular cross-orientation suppression, and taking into account that the latter is reduced by bicuculline iontophoresis at low temporal frequencies (see Fig. 6B,D), it is conceivable that interocular suppression involves exclusively cortical circuitry, whereas monocular suppression additionally invokes a subcortical mechanism, which becomes predominant at higher drift rates.
In normal cat area 17, orientation selectivity of binocular interactions is achieved by superimposition of highly stimulus-specific binocular facilitation (both with respect to orientation and spatial phase) on a background of rather nonspecific interocular suppression (Sengpiel, Freeman, and Blakemore 1995). Presumably, those facilitatory interactions form the basis of binocular fusion and stereopsis. Interestingly, there appears to be a graded loss of facilitation among area 17 neurons in strabismic cats, which is correlated with their degree of conventionally defined binocularity (see Fig. 2). This graded loss has a parallel in variations of the depth of strabismic suppression across the visual field in strabismic humans (Sireteanu and Fronius 1981). It is likely that the susceptibility to a breakdown in binocular facilitation is greatest in the center of the visual field, where cortical neurons have the smallest receptive fields, and therefore binocular convergence of inputs is lost with the smallest misalignment of the visual axes (Sengpiel and Blakemore 1996). Hence, it is here where perceptual suppression is strongest (Sireteanu 1982).
Anatomical Substrates of Strabismic Suppression
In view of the fact that suppression in strabismic cats is largely independent of the orientation and spatial phase of the suppressive stimulus, the inhibitory inputs responsible are likely to derive from a pool of cells with somewhat scattered receptive fields and a wide range of preferred orientations and spatial frequencies. We propose that suppression is based upon inhibitory horizontal connections between neighboring ocular dominance columns dominated by the right and left eyes. These projections should therefore extend across at least 1 ocular dominance column width (
500 µm).
The vast majority of all synaptic inputs (both excitatory and inhibitory) in area 17 have been found to originate within <500 µm of the recorded neurons (Roerig and Chen 2002), that is, local to a functional cortical column. Of the numerous types of inhibitory cortical interneurons (for review, see Markram and others 2004), the only group of cells that provide long-range horizontal connections of the sort stipulated by our hypothesis are large basket cells (Kisvárday 1992). Basket cells constitute roughly half of all inhibitory neurons, targeting the somata and proximal dendrites of pyramidal neurons and interneurons; among those, large basket cells are the primary source of lateral inhibition across columns within the layer that contains their somata (Kisvárday 1992; Markram and others 2004). A number of studies have related basket cell projections to the area 17 functional architecture (for review, see Kisvárday and others 2000). Although the local projections of layer 4 clutch cells as well as of layer 2/3 medium-sized basket cells are predominantly found in iso-orientation target sites, the long-distance (>500 µm) projections of layer 3 large basket cells are somewhat biased toward cross-orientation sites (Buzás and others 2001). This is in broad agreement with a photostimulation study in ferret area 17 showing that short-range synaptic inputs tend to be iso-oriented, whereas longer range inputs are more evenly distributed across orientation domains (Roerig and Chen 2002). Overall, inhibitory connections are more common than excitatory connections among cortical locations differing in orientation preference (Kisvárday and others 1997). Moreover, the (shorter) projections of medium-sized basket cells are mainly found in same-eye ocular dominance domains, whereas the long-distance projections of large basket cells contact both same- and opposite-eye domains (Buzás and others 2001).
At first thought, our hypothesis seems to be at odds with anatomical studies showing that intrinsic horizontal connections between OD columns are selectively lost in area 17 of strabismic cats and monkeys (Löwel and Singer 1992; Burkhalter and Tychsen 1993). However, retrograde labeling primarily indicates the origins of excitatory projections to the injection site because inhibitory connections form only a small fraction of all intrinsic projections in striate cortex. This is in agreement with a loss of stimulus-specific binocular facilitation, which we observed in the majority of cells recorded in strabismic cats (see Figs. 1 and 4). Therefore, the reduction in horizontal connectivity between columns of opposite eye dominance observed in strabismic animals may well be due to a selective loss of excitatory but not inhibitory connections (see Levi and others 1979).
It remains to be seen whether perceptual suppression can indeed be reduced by antagonizing intracortical inhibition (or strengthened by increasing inhibition). Even more intriguing is the possibility of testing, in an animal model, the long-standing hypothesis of a causal link between suppression and strabismic amblyopia.
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Acknowledgments |
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This work was supported by grants of the Medical Research Council (UK) to FS and by the German Research Foundation (DFG) SFB 509, TP C4 to UTE.
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