Ординатура / Офтальмология / Английские материалы / Eye, Retina, and Visual System of the Mouse_Chalupa, Williams_2008

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Plasticity of circuits in the visual cortex has traditionally been studied in several groups of higher mammals with an elaborate visual system. More recently, the mouse has been adopted by a number of researchers in the field. This trend is in part due to the ease of genetic interventions in this species, but there are other practical advantages to studying cortical plasticity in mice, such as their small size and fast generation time, as well as the fact that their genome has been completely sequenced. Moreover, recent experiments show that various aspects of mouse visual system function and plasticity can be readily assessed using behavioral tests (Prusky et al., 2000).

Several standard paradigms have been used to alter the sensory inputs to the visual cortex and thus induce plasticity, among them stripe rearing, squint induction, and focal retinal lesions. By far the most widely used manipulation is monocular deprivation (MD), the temporary closure of one eye. MD results in an overall strengthening of the open eye’s and a weakening of the closed eye’s representation in the visual cortex. In higher mammals, which possess ocular dominance (OD) columns, the effects of MD can be conveniently read out by observing, either with anatomical or with functional methods, the widening or shrinking of the open and closed eye columns, respectively (Shatz and Stryker, 1978; Hata and Stryker, 1994; Kind et al., 2002). Because mice do not have OD columns, the effects of MD must be assessed by other techniques. In the first part of this chapter we describe the various techniques that have been developed to determine OD in mouse visual cortex. We then focus on a specific aspect of OD plasticity in the mouse that has recently become overt, namely that the adult mouse visual cortex also shows considerable plasticity. Finally, we discuss recent results from our laboratory which show that the potency for plastic changes in mouse visual cortex can be strongly increased by prior episodes of plasticity.

Methods to assess ocular dominance plasticity in mouse visual cortex

Single-Unit Recordings Extracellular single-cell recordings are the most widely used method to determine OD, as well as other response properties of neurons in mouse visual cortex (Dräger, 1978; Gordon and Stryker, 1996; Hensch et al., 1998). They provide an unequivocal measure (the number of spikes) of a neuron’s response to stimulation

of either eye, which can be used to calculate a response bias for each individual cell. Provided that spikes from multiple units are reliably separated, this method also allows determining the exact proportion of binocular versus monocular neurons, which changes in a characteristic fashion after certain manipulations such as squint induction or alternating reverse occlusion (Gordon and Stryker, 1996). Moreover, the location of recorded cells in the visual cortex can be determined to a good extent, such that layer-specific differences in the degree of plasticity can be assessed (Gordon and Stryker, 1996).

A potential source of error in single-cell recordings is that they are prone to sampling biases. This is of particular concern when small numbers of cells are recorded from an area with a nonrandom distribution of response properties. This is the case in mouse visual cortex, since its binocular region is relatively small, with a rather smooth transition to monocular visual cortex. Thus, the extent of the binocular cortex must be mapped first to ensure that recordings are confined to this part. Another major disadvantage of singlecell recordings is that it is hard to make statements about absolute levels of response strength. The main reason is that typically, the visual stimuli used to determine OD are not optimized in every respect for a given cell, resulting in a large variation in total spike count between cells. This wide variation in overall apparent response strength, in combination with a limited number of recorded cells, makes statistical comparisons difficult. Consequently, in most single-cell recording studies from mouse visual cortex, OD is always expressed as the ratio between contralateral and ipsilateral eye responses (but see Gordon and Stryker, 1996).

Visually Evoked Potentials A number of studies have employed recordings of visually evoked potentials (VEPs) to determine function and plasticity in mouse visual cortex (Huang et al., 1999; Porciatti et al., 1999; Sawtell et al., 2003; Frenkel and Bear, 2004). VEP recordings allow the rapid measurement of basic parameters of mouse visual system, such as grating acuity and contrast response function, which were found to be in good agreement with behavioral or single-cell data (Porciatti et al., 1999). OD can be readily assessed with VEPs, and, unlike single-cell recordings, VEPs provide a reliable measure of the absolute response amplitudes elicited by stimulation of either eye (Sawtell et al., 2003; Frenkel and Bear, 2004). Moreover, VEPs can

be recorded relatively easily in awake mice (Sawtell et al., 2003; Frenkel and Bear, 2004), an advantage that turned out to be crucial for the discovery of OD plasticity in adult mice, which seems to be occluded by certain anesthetics. Because VEPs constitute a population signal from many neurons, however, they have a limited spatial resolution, and they do not permit the determination of receptive field (RF) parameters of individual neurons, such as orientation selectivity.

Optical Imaging Several recent studies have used optical imaging to obtain an overall measure of the strength of the representation of both eyes in mouse visual cortex (Cang et al., 2005; Hofer et al., 2006; Heimel et al., 2007). Optical imaging of intrinsic signals is based on a small decrease in light reflectance of neuronal tissue after its activation, which is in part caused by changes in blood oxygenation level and blood volume. It is ideally suited for the rapid mapping of topography in mouse visual cortex (Schuett et al., 2002; Kalatsky and Stryker, 2003) and thus can be used to determine the exact location of the binocular visual cortex in individual mice (figure 36.1). With this technique, we were

able to demonstrate strong and fully reversible OD shifts in adult mouse visual cortex, as well as a priming effect of prior MD episodes on later plasticity (Hofer et al., 2006). In juvenile mice, we employed optical imaging to systematically assess the effect of MD duration on the magnitude of the OD shift (figure 36.2). Optical imaging allows repeated measurements to be made in the same animal over extended periods of time (more than a year), such that the responses of individual mice to multiple epochs of MD-induced shifts and recovery can be followed. Long-term imaging in mice is greatly facilitated by the fact that the skull is sufficiently thin and transparent to allow recording of high-quality signals through the closed skull, which minimizes perturbation of cortical tissue. Of note, the reflectance changes measured with optical imaging provide an absolute measure of the activity evoked by each eye, which turns out to be highly reproducible between acutely imaged animals (Hofer et al., 2006).

Levelt and colleagues (Heimel et al., 2007) have recently described several improvements for optical imaging of MDinduced shifts in mouse visual cortex. By introducing a “reset” stimulus in a different part of the visual field between

Figure 36.1 Retinotopic mapping of mouse binocular visual cortex using optical imaging of intrinsic signals. A, Schematic illustration of primary visual pathway in the mouse, depicting the location of the dorsal lateral geniculate nucleus (dLGN) and the primary visual cortex (V1), with the binocular zone (bV1) located laterally. B, Top, Cortical blood vessel pattern as imaged through the skull. Bottom, Arrangement of grating stimuli used to map the central visual field. Color denotes stimulus position. C, Individual

activity maps displaying responses to the 3 × 3 stimulus grid depicted in B are presented separately to the two eyes. The coordinates of the cross are fixed in each map. D and E, Color-coded maps of the combined responses to contralateral (D) and ipsilateral (E) eye stimulation superimposed on the cortical blood vessel pattern, revealing the extent of the binocular zone. Color indicates stimulus position eliciting the strongest response at each pixel. Scale bars = 0.5 mm. See color plate 25.

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Figure 36.2 Optical imaging of MD-induced OD plasticity during the critical period. A, Schematic of stimulus arrangement. B–D, Ipsilateral (left) and contralateral (right) eye responses from the central region of the binocular visual cortex to stimuli shown in A from a normal P35 mouse (B), following MD (P26–P30) of the contralateral eye (C), and 46 days after a 4-day MD (D). Scale bar = 1 mm. E, OD shifts after MD (starting at P26–P28) shown as the

subsequent data acquisition trials, they were able to shorten the overall data acquisition time. In addition, normalizing visually evoked reflectance changes to a reference region outside the visual cortex greatly reduced the variability of responses, resulting in a reduction in the number of repetitions needed to obtain a reliable response.

The previously mentioned studies (Hofer et al., 2006; Heimel et al., 2007) employed a standard optical imaging paradigm, which consists of repeated brief (seconds) episodes of visual stimulation and data acquisition, each followed by a short interval without stimulation, during which the optical signal relaxes. An alternative method for optical imaging data acquisition has been introduced by Kalatsky and Stryker (2003). In this method, images from the visual cortex are continuously acquired as a bar is repeatedly swept across the visual field at a certain frequency. Fourier decomposition of the signal time course is then used to determine for each cortical region the power of the stimulation frequency, which is a measure of the activity evoked by the stimulus. Cang et al. (2005) have demonstrated that this optical imaging paradigm can be conveniently used to measure OD plasticity in mice.

In addition to overall reflectance changes, neuronal activity also results in an increased endogenous fluorescence of

ratio of contralateral to ipsilateral eye responses from individual animals (circles) plotted against MD duration. Dashed line shows average from nondeprived controls. F, Contralateral/ipsilateral ratio values for normal juvenile mice, after 4–10 days of MD, and 4–7 weeks after a 4- to 5-day MD. Horizontal lines indicate mean group values. Solid symbols are data points from the experiments shown in B, C, and D.

flavoproteins (Shibuki et al., 2003), which has been used to measure OD plasticity in the mouse (Tohmi et al., 2006). Similar to reflectance-based optical imaging, flavoprotein imaging allows measuring absolute response levels, as well as obtaining multiple recordings from the same animal.

As with VEPs, optical imaging is a population measure and thus has the disadvantage that it cannot be used to determine single-cell properties.

Calcium Imaging with Two-Photon Microscopy A method that combines the advantages of single-cell recordings with those of population measures such as VEPs or optical imaging is two-photon-based calcium imaging (Regehr and Tank, 1991; Stosiek et al., 2003; Ohki et al., 2005). After bulk injection of a membrane-permeable calcium indicator dye into the visual cortex, the labeled cell bodies of hundreds of individual neurons can be visualized by two-photon microscopy. Upon activation by a visual stimulus, intracellular calcium levels rise, and the indicator dye glows brighter (figure 36.3). We have used this method to study MD effects in mouse visual cortex and have found that shifts in OD can be reliably detected (Mrsic-Flogel et al., 2007). The magnitudes of the OD shifts observed in juvenile mice were very similar to the ones obtained with electrical single-cell

Figure 36.3 Mapping OD in mouse binocular visual cortex by two-photon calcium imaging. A, Examples of visually evoked calcium transients (fluorescent change, F/F) recorded from two different neurons in the binocular visual cortex loaded with the calcium indicator dye OGB-1AM. Thin traces show individual responses to stimulation of each eye; thick traces are average responses to eight stimulus presentations. Stimulation periods are indicated by gray bars. B, Response maps ( F) for the contralateral (left panel ) and ipsilateral (right panel ) eye 230 μm below the pial surface in a normal mouse. C, A cell-based OD map computed from the single-

recordings. Because of the very large number of recorded cells (several thousands from a small number of mice), we were able to determine absolute response levels for each eye in normal as well as MD mice. Of note, two-photon calcium imaging also allows the exact spatial localization of each imaged neuron in the visual cortex such that detailed maps of response properties at cellular resolution can be generated (Ohki et al., 2005, 2006). Figure 36.3 shows examples of color-coded OD maps from normal and MD mice. In line with previous studies (Dräger, 1975; Schuett et al., 2002), there is no obvious, strong organization for OD in mouse visual cortex. Closer inspection of such maps reveals, however, that in most mice there is a weak tendency for a clustering of cells dominated by the same eye (figure 36.3D).

So far we have not succeeded in imaging calcium signals repeatedly from the same mouse. This drawback might be overcome once genetically encoded calcium indicators with high signal-to-noise ratios become available for routine use in mammals (Griesbeck, 2004). Another disadvantage of

eye response maps in B. Individual neurons are color coded by the OD score, as indicated by the labels in D. OD score of 1 or 0 denotes exclusive response to contralateral or ipsilateral eye stimulation, respectively, and a value of 0.5 indicates an equal response to both eyes. D, Overlay of cell-based OD maps at different depths for a normal mouse (left, four depths, 190–290 μm), after a 5-day contralateral MD (center, six depths, 195–410 μm), and after a 5-day ipsilateral MD (right, two depths, 200 and 225 μm). Note weak clustering of cells with similar OD values in the normal mouse. Scale bars = 50 μm. See color plate 26.

two-photon calcium imaging is that the changes in calcium concentration occur relatively slowly, which makes it difficult, though not impossible (Kerr et al., 2005), to extract the exact number of action potentials from these signals. It follows that great care must be taken to isolate the fluorescence signals of individual cell bodies from changes of the surrounding neuropil, which might otherwise obscure a neuron’s specific response characteristics.

Gene Expression In addition to the functional methods in the previous section, MD effects have also been studied by mapping the expression of activity-related genes, such as Arc (Tagawa et al., 2005) or c-fos (Pham et al., 2004), in histological sections. Although this approach is limited by the fact that in a given mouse, only one stimulus parameter can be tested, it has the advantage that MD-induced changes in activity levels can be assessed in all regions of the cortex, in different cortical layers, and in other parts of the brain, for example the lateral geniculate nucleus (LGN). A variety

of additional genes have recently been described that are specifically induced by deprivation paradigms and thus could potentially be used to visualize OD shifts (Majdan and Shatz, 2006; Tropea et al., 2006).

Adult ocular dominance plasticity

The classic studies of MD in kittens by Wiesel and Hübel (1963) led to the notion of the critical period for OD plasticity in the visual cortex, which ends around the onset of adolescence. In line with this, in their quantitative assessment of MD effects in mice using single-unit recordings under barbiturate anesthesia, Gordon and Stryker (1996) described a critical period for OD plasticity that peaks around 4 weeks of age and terminates soon after. However, a large body of literature supports the fact that in principle, the neocortex maintains its capacity for plasticity throughout life. Studies in the visual, auditory, and somatosensory cortex have demonstrated robust experience-dependent reconfiguration of neuronal response properties in adult animals after a variety of manipulations of sensory inputs (Fox and Wong, 2005). This is probably best exemplified by the dramatic reorganization of RFs and synaptic connections in the visual cortex after restricted retinal lesions (Kaas et al., 1990; Darian-Smith and Gilbert, 1994; Giannikopoulos and Eysel, 2006). The recent finding of strong OD plasticity in adult mice well beyond the traditional critical period is therefore not entirely unexpected (Sawtell et al., 2003; Pham et al., 2004; Tagawa et al., 2005; Frenkel et al., 2006; Hofer et al., 2006). Adult OD plasticity was first shown by Sawtell and colleagues (2003) in awake adult mice using VEP recordings. Subsequently, adult OD shifts were also demonstrated in anesthetized mice with several other methods, including extracellular microelectrode recordings (figure 36.4; Hofer et al., 2006), optical imaging of intrinsic signals (see figure 36.4; Hofer et al., 2006; Heimel et al., 2007) and VEP recordings (Pham et al., 2004). A study using the activity reporter gene Arc to assess functional eye representation in mouse visual cortex additionally showed MD effects before and after the traditional critical period (Tagawa et al., 2005). Taken together, these results show that OD shifts in mice occur well into adulthood.

OD plasticity in adult mice, however, is different from that in juvenile animals in that it requires longer MD durations, since MD periods of 4 days or less are not especially effective in shifting OD in adults (Fagiolini and Hensch, 2000; McGee et al., 2005; Hofer et al., 2006; Tohmi et al., 2006). Although there is some debate as to why some studies have not reported robust OD plasticity in adult animals, these differences might be attributed either to the use of MD durations that are too brief (≤4 days; e.g., Tohmi et al., 2006) or to different anesthesia regimens (Pham et al., 2004; Heimel et al., 2007). Interestingly, barbiturate anesthesia,

which normally boosts GABAergic transmission, may obscure the expression of OD plasticity specifically in adults. This point is underscored by another study in adult mice showing a masking effect of fentanyl-based anesthesia on OD plasticity (Heimel et al., 2007). Considering that different anesthetics act differentially on various neurotransmitter systems in the brain, these results support the view that distinct mechanisms may underlie OD shifts in juvenile and adult animals.

Thus far, robust adult OD plasticity has been observed only in mice, a species that lacks OD columns. In rats, which have a visual system similarly organized to that of mice, single-unit recordings have not demonstrated adult OD plasticity after 7 days or more of deprivation (Pizzorusso et al., 2002). However, partial OD shifts are nonetheless possible in rats beyond 7 weeks of age (Guire et al., 1999; He et al., 2006). In cats, OD shifts can be induced up to a year of age, but with deprivation periods lasting 3 months (Daw et al., 1992). The clear results demonstrating strong adult OD plasticity in mice should prompt a reexamination of the degree of adult plasticity in these species with different MD durations and anesthetic regimens.

Mechanisms of juvenile and adult ocular dominance plasticity

In juvenile mice, OD shifts are mediated both by an early loss of deprived-eye responsiveness and a delayed gain of open-eye responsiveness (Frenkel and Bear, 2004). Deprivedeye response depression in juvenile mice likely results from the weakening of intracortical synaptic connections serving the deprived eye (Rittenhouse et al., 1999; Heynen et al., 2003; Frenkel and Bear, 2004; Mataga et al., 2004) and may rely on N-methyl-d-aspartate (NMDA) receptor-dependent long-term depression (LTD) of excitatory synapses (Heynen et al., 2003) or on long-term potentiation (LTP) of local inhibitory transmission (Maffei et al., 2006), the maturation of which is important for triggering OD plasticity (Hensch, 2005).

The gain of visual drive from the nondeprived eye could be mediated equally well by LTP of intracortical excitatory connections (Abraham and Bear, 1996) or by nonHebbian, homeostatic mechanisms (Miller, 1996; Turrigiano and Nelson, 2004). It has been proposed that strengthening of nondeprived-eye synapses could be facilitated by promoting the induction of LTP in favor of LTD (Kirkwood et al., 1996), as specified by the Bienenstock-Cooper- Munro theory, which entails a sliding synaptic modification threshold based on the history of postsynaptic activity (Bienenstock et al., 1982; Abraham and Bear, 1996). In support of this LTP-based model, OD plasticity is partially blocked in adult NMDA receptor knockout mice (Sawtell et al., 2003). Although this suggests that MD-induced strengthen-

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Figure 36.4 OD plasticity in adult visual cortex assessed with intrinsic signal imaging and multielectrode recordings. A and B, Ipsilateral and contralateral eye responses in the same mouse before (A, P80, contralateral/ipsilateral ratio = 2.21) and after 6 days of MD (B, P92, contralateral/ipsilateral ratio = 1.09). Stimulus arrangement as in figure 36.2A. C, Ratio of contralateral to ipsilateral eye response strength after 6–7 days of MD in normal adult mice plotted against age shows no significant correlation. R2 = 0.12, P = 0.24. D, Contralateral/ipsilateral ratio values from repeated experiments in adult control animals (gray, interimaging period

ing of open-eye responses may be Hebbian in nature, more work is needed to forge a causal link between LTP and openeye response potentiation.

In principle, open-eye responses could also be strengthened through homeostatic mechanisms. The concept of homeostatic plasticity is founded on the assumption that neurons engage mechanisms that maintain their responsiveness within a certain range in response to global alterations of neuronal activity levels (Burrone and Murthy, 2003; Turrigiano and Nelson, 2004). Consistent with this notion,

1–3 weeks) and in deprived adult animals before and after 6 days of MD in the contralateral eye (black). E, Functional map of the binocular region (green corresponds to the ipsilateral eye representation), used for targeting electrode penetrations (circles). Scale bar = 0.5 mm. F, Distribution of contralateral/ipsilateral ratio values from all recording sites in adult control (2.99 ± 0.28, mean ± SEM, 324 recording sites, 4 mice) and deprived (1.05 ± 0.12, 260 recording sites, 5 mice) animals, showing strong OD shifts in response to MD. Each color represents a different animal. Horizontal lines indicate mean group values. See color plate 27.

visual deprivation increases the strength of excitatory synapses and the excitability of neurons in rodent monocular cortex (Desai et al., 2002; Maffei et al., 2004), where no interocular interactions occur. In principle, such changes are well suited to counteract the chronic reduction of visual drive by increasing neuronal responsiveness. In fact, using two-photon calcium imaging and electrical multi-unit recordings, we found direct in vivo evidence for homeostasis of visually evoked responses in monocular and binocular visual cortex after MD (Mrsic-Flogel et al., 2007). Specifi-

cally, the responses of monocular neurons responding exclusively to the deprived eye after MD were larger than those of monocular neurons in nondeprived animals.

Although robust OD shifts in the adult visual cortex occur after longer MD durations, adult OD plasticity is not equivalent to that of juvenile animals (Sawtell et al., 2003; Lickey et al., 2004; Pham et al., 2004; Tagawa et al., 2005; Frenkel et al., 2006; Hofer et al., 2006). For example, not all studies have reported a significant loss of deprived-eye responsiveness in the hemisphere contralateral to the deprived eye (Hofer et al., 2006). The reasons for this difference are unclear. The lack of response depression could be explained by differences in recording methods or anesthetic regimens. Alternatively, it may reflect an age-related decline in the capacity of visual cortex to express LTD at excitatory synapses (Kirkwood et al., 1997; Heynen and Bear, 2001). Consistent with this idea, the loss of spines on layer 2/3 pyramidal neurons in juvenile mice after 4 days of MD does not occur in adults (Mataga et al., 2004).

Prior experience enhances adult ocular dominance plasticity

What are the long-term consequences of OD plasticity in the visual cortex? In mice and other species, restoration of normal binocular vision after a period of MD functionally restores normal binocular responses (Mitchell et al., 1977; Kind et al., 2002; Liao et al., 2004; Hofer et al., 2006). We recently tested whether an OD shift earlier in life affects the capacity of the visual cortex for subsequent plasticity (Hofer et al., 2006). In naive adult mice, 3 days of contralateral eye MD was not sufficient to induce measurable OD plasticity (figure 36.5). However, the same duration of MD resulted in a marked shift of OD in mice that had experienced MD of the same eye up to 2 months earlier (figure 36.5). Notably, this apparent enhancement of adult plasticity occurred irrespective of whether the first deprivation occurred in juvenility or in adulthood. Moreover, OD shifts induced by a second MD episode persisted longer after reopening of the eye. These results indicate that prior MD leaves a lasting mark in the binocular visual cortex such that subsequent OD shifts emerge faster and last longer. The capacity for plasticity in the mammalian cortex can therefore be enhanced by past experience.

In principle, two types of mechanisms could account for the facilitation of OD plasticity just described. Prior MD experience could lead either to a general increase in cortical plasticity or to specific changes in the circuits or synapses affected by the initial deprivation. We found that the enhancement of plasticity was apparent only after repeated deprivation of the same eye, since MD of the other eye 3–4 weeks later did not lead to an improved OD shift, and in fact entirely abolished its occurrence after longer deprivation

A

Figure 36.5 Prior MD in adult mice facilitates subsequent OD plasticity. A, Experimental timelines for assessing the effect of repeated adult MD in the contralateral eye. B, Strong OD shifts after 6–7 days of MD in adult mice recover completely with restored binocular vision (imaged 8–30 days after eye reopening). Reclosure of the eye results in strong OD shifts even after 3 days, unlike in naive mice (P < 0.001). Horizontal lines indicate mean group values. Lines connect data points from mice imaged repeatedly.

periods (figure 36.6). These findings indicate that prior deprivation does not increase cortical plasticity in general to any input, as has been observed after dark rearing (Cynader and Mitchell, 1980) or after pharmacological manipulations (Pizzorusso et al., 2002). Instead, they provide evidence for specific changes in cortical circuitry that support the facilitation of OD shifts only in the same direction as experienced earlier in life, while rendering shifts in the opposite direction less effective.

These results argue for a specific trace that is laid down in visual cortex during the first period of plasticity. This trace is not functionally apparent in the intervening period of several weeks but rather requires a second MD to be disclosed. What is the nature of this trace? Prior MD experience could establish changes in the form of lasting biochemical or structural modifications that are (re)activated on the second MD. For instance, activity-dependent changes in visual cortex associated with the initial MD episode could lead to the generation of new synapses that might be disabled functionally during the recovery, which would subsequently facilitate future circuit adaptations.

The view that structural changes might form the basis for the facilitation of OD plasticity is supported by closely related observations in the barn owl’s auditory localization system (Knudsen, 1998). Here, the capacity for plasticity of auditory midbrain neurons in response to a prism-induced visual field displacement was extended into adulthood if the owls had a similar prism experience as juveniles. The shifts of auditory

3 / 7 d MD ipsi

3 / 7 d MD ipsi

B

MD ipsilateral eye

DRepeated MD contra - ipsi

Figure 36.6 Facilitatory effect of repeated MD is eye specific. A, Experimental timelines for successive MD of opposite eyes. B, In naive adult mice, contralateral/ipsilateral ratio values increased marginally after 3 days of MD and strongly after 7 days of MD of the ipsilateral eye. C, Response strength of each eye for the same conditions as in B. D, Previous 7-day MD of the contralat-

space fields in adult owls is explained by the formation of new axonal connections during initial prism rearing (DeBello et al., 2001) that are physically maintained but functionally disabled after removal of the prisms and the shifting back of auditory space fields (Linkenhoker et al., 2005). In mouse visual cortex, too, MD can result in anatomical changes, which have been observed at both the presynaptic level (Antonini et al., 1999) and the postsynaptic level (Mataga et al., 2004; Oray et al., 2004). It is therefore tempting to speculate that these structural changes might outlast the first MD, facilitating the OD shift induced by the second episode of MD.

This idea can be tested experimentally. In vivo twophoton imaging of synaptic structures could be used to test

eral eye and subsequent recovery did not accelerate plasticity in response to a 3-day ipsilateral eye closure. In contrast, prior deprivation impaired OD plasticity induced by a 7-day ipsilateral MD. Open circles denote data from individual animals; horizontal lines indicate mean values. E, Response strength of each eye for the same conditions as in D. Error bars indicate SEM.

whether spines that are gained during the first MD episode are maintained after reopening of the eye, forming a structural memory of the altered sensory input. The second MD episode might consequently result in only a small increase in newly formed spines. This scenario further raises the question of how these persistent contacts are functionally suppressed after recovery from the first MD. In principle, this could be brought about by specific inhibition of these connections. Alternatively, they could be rendered ineffective by converting them into silent synapses by the removal of AMPA receptors (Malenka and Nicoll, 1997), which could be tested by comparing the ratio of AMPA to NMDA currents in neurons obtained from normal and previously deprived mice.

Behavioral correlates

Changes in cortical circuitry following MD are important for visual behavior in rodents. An imbalance in binocular inputs early in postnatal life can lead to the development of poor visual acuity (Muir and Mitchell, 1973; Prusky and Douglas, 2003), which primarily affects the deprived eye (Iny et al., 2006). Longer deprivation periods in rats and MD in adult mice can lead to improvement in the spatial acuity of the spared eye (Iny et al., 2006; Prusky et al., 2006). Interestingly, the onset and persistence of the enhancement of spatial vision can be further improved after repeated MD in adult mice (Prusky et al., 2006), a result consistent with the effects of prior MD on subsequent OD plasticity (Hofer et al., 2006). These behavioral findings are in close keeping with the loss of deprived-eye function and the gain of nonde- prived-eye function in the contralateral visual cortex after juvenile and adult MD, respectively. The MD paradigm in mice, therefore, provides a useful general model for studying the mechanisms underlying plasticity of cortical circuits and related behaviors.

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