Kathryn M. Murphy,1,2 Christopher Trepel1 & Victor D. Pegado1
McMaster University, Departments of Psychology1 and Biomedical Sciences2
1280 Main St. West, Hamilton ON L8S 4K1 Canada
Methods: To examine this possibility we used immunohistochemical techniques to label the NMDAR1 receptor subunit protein in kitten visual cortex. The arrangement of the NMDAR1 subunit was visualized (using a monoclonal antibody) in flattened and coronal sections through visual cortex. The tangential and laminar distributions of NMDAR1 immunoreactivity (NMDAR1ir) were studied at the peak of the critical period for plasticity (4-5 weeks of age) in the developing kitten visual cortex.
Results: At the ages examined there was a non-uniform distribution of NMDAR1 immunoreactivity in the visual cortex. These patches of darker NMDAR1 label were found in layers 2/3 and extended up into layer 1. Thus, during development neurons expressing the NMDAR1 receptor subunit were distributed in a patchy fashion in the upper layers of the kitten visual cortex.
Conclusions: This suggests that NMDA-mediated activity-dependent plasticity may not occur uniformly across the tangential extent of the visual cortex, and raises the possibility that the arrangement of NMDAR1 patches may guide the emergence of nascent columns in the developing visual cortex.
The familiar columnar organization of the visual cortex develops through progressive refinement of cortical connections and receptive field properties. For example, ocular dominance columns emerge during the critical period for plasticity in postnatal development when the initially overlapping geniculocortical afferents segregate into alternating right- and left-eye columns (24, 36, 43). This process of afferent segregation is dependent both on the pattern of retinally driven activity and on the presence of NMDA receptors in the visual cortex. Numerous studies have shown that the NMDA receptor subclass of the excitatory amino acid glutamate is a key post- synaptic element in the mediation of activity-dependent rearrangement of inputs to the developing visual system (14, 16, 28). For example, changes in the lateral geniculate nucleus (20) and cortical receptive field properties (4, 9) typically associated with monocular deprivation are substantially reduced or prevented when the NMDA receptor is blocked. In addition, a well known mechanism of cortical and subcortical use-dependent plasticity, long-term potentiation (LTP), which is dependent upon NMDA receptor activation, can be induced in the visual cortices of rats (2, 3, 31, 32) and cats (5, 8, 21). Additional support for the role of the NMDA receptor in developmental changes in the visual cortex comes from anatomical studies that have demonstrated an increased binding of autoradiographic probes to the NMDA receptor during the critical period (6, 19). These autoradiography studies have elucidated certain aspects of the regional and laminar distributions of NMDA receptor during development of the visual cortex, however, the specificity of the probes and the inability of these methods to achieve cellular resolution have left unanswered certain questions about the arrangement of neurons expressing NMDA receptor during development of the visual cortex. These problems can now be overcome with the use of immunohistochemical techniques in conjunction with monoclonal antibodies to the NMDAR1 subclass of the NMDA receptor (1, 25, 46).
The precise role of activity and, consequently, the importance of the NMDA receptor for the formation of the tangential pattern of columns in the visual cortex, has been questioned by a series of recent reports indicating that aspects of the overall organization of orientation columns (17), ocular dominance columns (22,26), and cytochrome-oxidase blob defined modules (30, 35, 40) are unchanged by manipulations that dramatically effect the pattern of retinally driven activity. These reports raise the possibility that features other than activity, possibly intrinsic to the cortex, play an important role in determining characteristics of the layout of cortical columns across the visual cortex. Can the notion of intrinsic features be linked with the activity-dependent rules for development of visual cortical columns? The present study explores the possibility of a link between intrinsic cortical modularity and the activity-dependence of cortical development by mapping the tangential and laminar arrangement of neurons expressing a fundamental NMDA receptor subunit (NMDAR1) at the peak of the critical period for columnar development in the kitten visual cortex. Our objective was to determine the tangential distribution of this anatomical component of activity-dependent plasticity and evaluate whether the spatial arrangement of neurons expressing the NMDAR1 receptor subunit could play a role in organizing the tangential pattern of cortical columns.
Materials and Methods
Animals and histology. The distribution of neurons expressing the NMDAR1 receptor subunit was examined in the developing visual cortex of 5 normally reared kittens at the peak of the critical period (4 - 5 weeks of age). Animals were euthanized with a lethal injection of Euthanol (sodium pentobarbital, 165mg/kg) and perfused transcardially with cold 0.1 M phosphate- buffered saline (PBS; 4oC, pH 7.4), followed by 2% paraformaldehyde in 0.1 M PBS (4oC) for 4 minutes. One hemisphere was unfolded and flattened as described previously (39, 41) while the other hemisphere was blocked in the frontal plane. Following flattening and blocking the tissue was postfixed in cold 2% paraformaldehyde and 30% sucrose in PBS for 6 hours, then transferred to 30% sucrose in PBS and stored overnight. Sections were cut on a freezing microtome, at a thickness of 50µm, either tangential to the pial surface from the flattened hemisphere or in the coronal plane through the intact hemisphere.
Immunohistochemistry. Standard immunohistochemical procedures were used to visualize the expression of NMDAR1 in sections through the visual cortex. Free-floating tangential and coronal sections were transferred to PBS and 2% bovine serum albumin containing mouse anti-NMDAR1 monoclonal antibody 54.1 (PharMingen, San Diego, CA, at a working dilution of 1:500). Sections were incubated in anti-NMDAR1 for 40 hours at 4oC with continuous agitation and immunoreactivity was visualized through the avidin-biotin process using Vectastain ABC elite kits (Vector Labs, Inc.) and the chromogen 3,3'-diaminobenzidine (DAB). Control sections were processed in the same manner except the anti-NMDAR1 was omitted. Sections were mounted onto slides and coverslipped with DPX (Aldricht Chemical Co.).
Analysis. Photomicrographs of the NMDAR1 immunoreactivity in area 17 were taken using Nomarski optics, transferred to PhotoCD (Eastman Kodak Co.) format, and the figures were composed using Photoshop (Adobe Systems Inc). Laminar boundaries were determined for the coronal sections by comparison with adjacent Nissl stained sections.
Examination of both coronal (Fig. 1) and tangential (Fig. 2) sections reveals a non-uniform, patchy distribution with dark patches of NMDAR1 immunostaining in areas 17 of the kitten visual cortex at the peak of the critical period (4-5 weeks of age). In coronal sections, the appearance of the dark patches of NMDAR1 immunoreactivity is that of columns oriented perpendicular to the pial surface and extending down through the supragranular layers of the visual cortex (fig. 1). Some of these NMDAR1 patches may dip into the superficial aspect of layer 4, however, no obvious patchiness has been observed in layers 4, 5 or 6. Thus, the non-uniform distribution of NMDAR1ir is confined to the supragranular layers, and within those layers the NMDAR1ir patches appear to be spaced at regular intervals (range 350- 900µm) comparable to the spacing of blobs (39) in cat visual cortex.
The laminar distribution of NMDAR1ir is very consistent at the ages examined (4-5 weeks of age), namely, layer 1 is relatively lightly stained, while layers 2/3 contain many darkly labeled pyramidal and some non-pyramidal neurons (Fig 3). Layer 4 has numerous small neurons that are NMDAR1ir, however, the neuropil staining is stratified with the superficial half more lightly labeled and a dark band of neuropil staining running through the ventral half of layer 4 (Fig. 4). In the infragranular layers, some darkly labeled large pyramidal neurons are apparent in layer 5, and layer 6 is composed of numerous NMDAR1ir neurons, especially in layer 6b (Fig. 5).
The composition of the label in the dark patches of NMDAR1ir in the supragranular layers is apparent at high magnification (Fig. 6). Many darkly labeled pyramidal neurons and their processes are found in the patches. NMDAR1 immunoreactivity is apparent on the cell bodies, as well as on the apical and basal dendritic processes of the pyramidal neurons. There is a tendency for labeled apical dendrites to be closely grouped together giving the appearance of bundles or clusters. Figure 6 shows the labeled cell bodies and processes in the superficial aspect of an NMDAR1 patch where it extends through layer 1 and into the top of layer 2. A dense mesh of fine NMDAR1 immunoreactive processes within the patch in layer 1 can be resolved with the Nomarski optics. The density of processes within a patch is higher than is found in the neighboring, non-patch, region. The dense array of processes observed in layer 1 arises from the dendrites of layer 2/3 NMDAR1-positive neurons that extend up into layer 1. Thus, it appears that the difference between the label found inside versus outside an NMDAR1 patch is largely due to the dense mesh of fine NMDAR1 positive processes that gives rise to the darker neuropil staining, in addition to the numerous darkly labeled cell bodies within a patch.
In this study we demonstrate that at the peak of the critical period for visual cortical plasticity the distribution of the NMDAR1 receptor subunit is patchy in the upper layers of kitten visual cortex. The patches of NMDAR1 immunoreactivity observed at 4-5 weeks of age extend through the supragranular layers, including layer 1, and are composed of darkly labeled cell bodies and dendritic processes, plus darker neuropil staining. The concentration of NMDAR1-positive apical dendrites in these patches contributes to the radial, columnar-like appearance of the staining pattern observed in coronal sections. This arrangement of the NMDAR1 receptor subunit in kitten visual cortex raises the possibility that synaptic plasticity, which is dependent upon NMDA-based mechanisms, could have a regular waxing and waning of efficacy across the developing supragranular layers of the visual cortex.
In general, the laminar distribution of the NMDAR1 receptor subunit that we observed in the developing kitten visual cortex is very similar to previous studies of the arrangement of the NMDAR1 receptor subunit in either developing rat visual cortex (1) or mature monkey visual cortex (25). In both of these studies, the densest labeling with a monoclonal antibody to NMDAR1 was observed in the superficial layers. Furthermore, Aoki et al. (1) report the presence of bundles of NMDAR1-positive apical dendrites in the developing superficial layers of the rat visual cortex which, upon visual inspection (see Figure 6C in ), are akin to the NMDAR1 patches that we observed in developing kitten visual cortex. The cellular resolution and increased specificity that can be attained with the use of a monoclonal antibody and immunohistochemical techniques to visualize the distribution of the NMDAR1 receptor subunit, versus autoradiographic techniques, are crucial for addressing issues of the tangential, laminar, cellular, and ultrastructural location of the NMDA receptor.
A variety of anatomical features and markers have been shown to be patchy in the cat visual cortex. Recently, we discovered cytochrome-oxidase blobs in the cat visual cortex (39), demonstrating that this fundamental feature of visual cortical columnar organization is not restricted to primates and furthering the notion that blobs may reflect a modular organization intrinsic to the cortex (30, 35). In addition, during early postnatal development, horizontal intrinsic connections emerge in the supragranular layers, where the NMDAR1 patches are found, and form a lattice-work of patchy connections in the visual cortex (7). Others also have noted transiently patchy markers for adenosine (45), serotonin (12) and zinc (11) at later stages in development. The presence of a patchy distribution of zinc and serotonin is of particular interest since they have been implicated or co-implicated, along with nitric-oxide (29, 38), in the regulation of glutamate binding to, or excitation at, the NMDA receptor. For example, physiological study has shown that zinc can have a direct action on NMDA-mediated excitatory transmission (13). Taken together, it seems plausible to propose that the NMDAR1 patches in layers 2/3 may unify these features during development by underlying both the patchy arrangement of these other markers, as well as mediating activity-dependent synaptic plasticity in the developing visual cortex.
The development of ocular dominance columns and their mutability in response to changes in visual experience is dependent, in part, upon plasticity that involves activation of the NMDA receptor (15, 33, 44). The patches of NMDAR1 receptor subunit immunoreactivity observed in kittens could contribute to the development of columnar systems by influencing the local efficacy of activity-dependent plasticity in cortical circuits and as a consequence guide the overall patterning of columns across the tangential extent of the visual cortex. This influence may be similar to the role that the cortical interaction function provides in computational models of column development (37). In models of ocular dominance column formation that are based upon local competitive Hebbian mechanisms, the cortical interaction function determines the pattern and extent of these local interactions and, through random perturbations in the initial strength of activity >from the eyes, the ocular dominance domains emerge. The interaction function promotes the clustering of the inputs from an eye and the development of the characteristic, millimeter wide, zebra stripe-like pattern of alternating eye preference. Without the cortical interaction function, the pattern of ocular dominance would take on a salt- and-pepper appearance where changes in ocular dominance would be on a neuron-by-neuron basis rather than the familiar columnar arrangement. The clustered horizontal connections in the supragranular layers of visual cortex (7) have been proposed as a biological correlate of the cortical interaction function (37). The NMDAR1 patches may also fulfill the role of the cortical interaction function through the waxing and waning of the level of local activity-dependent synaptic plasticity that would necessarily occur for the cortical circuits within versus outside a patch. The function of waxing and waning of the plasticity of cortical circuit upon column development could either directly influence changes in layer 4 or indirectly influence layer 4 by effecting the organization of columnar circuits outside of layer 4. For example, the NMDAR1 patches may participate in the specific refinement of the clustered horizontal connections within the supragranular layers. Preliminary investigations indicate that NMDAR1 patches are present in supragranular layers at 2 weeks of age (47), before ocular dominance column segregation has begun (36) and at a time when the patchy nature of the horizontal connections is in the process of refinement (7). Determining the time course and relationship of the NMDAR1 patches to the intrinsic horizontal connections, as well as other aspects of the columnar circuitry, will be important for understanding the significance of the NMDAR1 patches for the development of cortical columns.
In the kitten, ocular dominance columns emerge during early postnatal development (36) and their formation is most susceptible to changes introduced in the visual environment at 4-5 weeks of age (42). The presence of the NMDAR1 patches in kitten visual cortex at these same ages is suggestive that their arrangement could interact with visually driven activity in the development of this columnar system. The emergence of ocular dominance columns in monkeys, however, begins prenatally and a recent study has shown that at birth their pattern is already adult-like (23). These results indicate that the arrangement of ocular dominance columns in monkey V1 is not dependent upon visual experience and so provide additional support for the notion that features intrinsic to the cortex, that are independent of the geniculocortical inputs and their activity, may specify the tangential pattern of cortical columns (22,26,27,30,35). It is important to note, however, that retinally driven activity is essential for the segregation of afferents into ocular dominance columns, and that in primates spontaneous retinal activity is present in utero. Since models of ocular dominance column formation indicate that spontaneous retinal activity can promote segregation into columns (37) this is likely an important element of the prenatal development of ocular dominance columns in monkeys. It cannot, however, explain why the overall pattern is adult-like at birth since models predict that spontaneous retinal activity alone lacks the necessary degree of interocular correlation to give rise to an adult-like pattern of ocular dominance columns (18). A plausible explanation can be found in a model that combines spontaneous retinal activity with a feature outside of the input layer, possibly NMDAR1 patches, that both provides the periodic template and interacts with retinally driven activity to guide the tangential patterning of visual cortical columns. Such a model would predict that an intrinsic feature, similar to the NMDAR1 patches found in kittens, would be present in V1 during prenatal development of monkeys.
Development of the columnar systems in the visual cortex involves a complex array of interdependent events that include the growth and refinement of afferent connections, the generation and differentiation of the neurons that form the layers and circuits of the cortex, and the pattern of retinally derived activity. These events are pulled together by the elaboration of synaptic structures that are specialized for the development and strengthening of contacts between neurons. The NMDA receptor has become one of the most prominent of these structures owing to its role in neuronal migration (34) and activity-dependent aspects of development in the central visual pathways (4, 14, 20, 33). Moreover, recent results indicate that during development of the hippocampus, the NMDA receptor may provide a blue-print, independent of sensory activity, for the formation of glutamatergic circuitry (10). Thus, our demonstration that the NMDAR1 receptor subunit is distributed in a patchy fashion in the developing visual cortex could provide a crucial link in determining the degree to which the role of the visual cortex is permissive versus instructive, by providing an intrinsic organization of cortical circuitry (27) during the development of cortical columns. In this scheme, the NMDAR1 patches could indicate patches of cortical circuitry most capable of supporting activity-dependent plasticity and, consequently, could guide the development and tangential layout of nascent columns.
We wish to thank Dr. David Jones for helpful discussions concerning these data. This work was support by a Natural Science and Engineering Research Council grant (OGP0170583) and McMaster Science and Engineering Research Board grant to KMM and a Natural Science and Engineering Research Council Scholarship to CT. KMM is an NSERC University Research Fellow and Alfred P. Sloan Research Fellow.
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47. Trepel, C, Pegado, VD, and Murphy, KM, Patchy distribution of the NMDAR1 receptor subunit in kitten visual cortex. Invest. Ophthal. Vis. Sci. Suppl., 37 (1996) 480.