Cerebral Cortex Advance Access originally published online on August 28, 2007
Cerebral Cortex 2008 18(5):1125-1138; doi:10.1093/cercor/bhm148
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Unusual Patch–Matrix Organization in the Retrosplenial Cortex of the reeler Mouse and Shaking Rat Kawasaki
1 Laboratory for Cortical Organization and Systematics, RIKEN, Brain Science Institute, Wako, Saitama 351-0198, Japan, 2 Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan, 3 Laboratory for Cell Culture Development, 4 Laboratory for Developmental Neurobiology, RIKEN, Brain Science Institute, Wako, Saitama 351-0198, Japan, 5 Department of Molecular Neurobiology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan, 6 Laboratory for Neurobiology of Synapse, RIKEN, Brain Science Institute, Wako, Saitama 351-0198, Japan, 7 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Osaka 560-0082, Japan, 8 Department of Anatomy and Developmental Neurobiology, Kobe University Graduate School of Medicine, Chuo-ku, 7-5-1 Kusunoki-cho, Kobe 650-0017, Japan, 9 Graduate School of Science and Engineering, Saitama University, Sakura-ku, Saitama-shi, Saitama, 338-8570, Japan
Address correspondence to Noritaka Ichinohe, MD, PhD, Laboratory for Cortical Organization and Systematics, RIKEN, Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Email: nichinohe{at}brain.riken.Jp.
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The rat granular retrosplenial cortex (GRS) is a simplified cortex, with distinct stratification and, in the uppermost layers, distinct modularity. Thalamic and cortical inputs are segregated by layers and in layer 1 colocalize, respectively, with apical dendritic bundles originating from neurons in layers 2 or 5. To further investigate this organization, we turned to reelin-deficient reeler mouse and Shaking rat Kawasaki. We found that the disrupted lamination, evident in Nissl stains in these rodents, is in fact a patch–matrix mosaic of segregated afferents and dendrites. Patches consist of thalamocortical connections, visualized by vesicular glutamate transporter 2 (VGluT2) or AChE. The surrounding matrix consists of corticocortical terminations, visualized by VGluT1 or zinc. Dendrites concentrate in the matrix or patches, depending on whether they are OCAM positive (matrix) or negative (patches). In wild-type rodents and, presumably, mutants, OCAM+ structures originate from layer 5 neurons. By double labeling for dendrites (filled by Lucifer yellow in fixed slice) and OCAM immunofluorescence, we ascertained 2 populations in reeler: dendritic branches either preferred (putative layer 5 neurons) or avoided (putative supragranular neurons) the OCAM+ matrix. We conclude that input–target relationships are largely preserved in the mutant GRS and that dendrite–dendrite interactions involving OCAM influence the formation of the mosaic configuration.
Key Words: cortical layer • corticocortical • cortical module • dendritic organization • thalamocortical • OCAM
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The rat granular retrosplenial cortex (GRS) is a simplified, limbic cortex with a sparse layer 4. Pyramidal cell dendrites and their afferent inputs have a highly organized laminar and modular geometry. This is particularly prominent in layer 1, where apical dendritic bundles, from neurons in layer 2, interdigitate with the apical dendritic tufts from pyramidal neurons in layer 5 (Wyss et al. 1990
; Ichinohe and Rockland 2002; Kaneko et al. 2002; Ichinohe et al. 2003; Miro-Bernie et al. 2006). Thalamic afferents, visualized by tracer injections or anti-vesicular glutamate transporter 2 (VGluT2) immunohistochemistry, target the dendritic bundles from layer 2 neurons in layer 1a,b. Intracortical projections (visualized by VGluT1) target layer 5 apical dendritic tufts in layer 1b,c (Wyss et al. 1990; Kaneko et al. 2002, Miro-Bernie et al. 2006). Modularity is not evident in the subjacent layers, but the laminar complementarity of inputs persists. Layers 3 and 4 are positive for VGluT2 and layers 5 and 6 for VGluT1 (Kaneko et al. 2002).
In a study of the postnatal developmental time course of dendritic aggregation, we established a significant role in this organization for the cell adhesion molecule OCAM (Ichinohe et al. 2003). OCAM, localized mainly on dendrites of layer 5 neurons, exhibits a patchy distribution in layer 1 from as early as P3 in the rat. This predates the conspicuous dendritic aggregates of layer 2 neurons by 2 days. On this bases, therefore, OCAM has been proposed to have homophilic adhesive effects among dendrites of layer 5 neurons and repellent effects on the interposed dendrites of layer 2 neurons (Ichinohe et al. 2003). In addition, we found that OCAM can serve as a convenient reference marker for corticocortical afferents (colocalizing with OCAM+ patches or layers) and thalamocortical afferents (corresponding to OCAM– patches or layers).
To further investigate this distinctive compartmental organization, we turned to the reelin-deficient mutant rodents, reeler mouse and Shaking rat Kawasaki (SRK). In these animals, the normal lamination is conspicuously disrupted, and dendrites are malpositioned (Caviness and Rakic 1978; Pinto Lord and Caviness 1979; Landrieu and Goffinet 1981; Aikawa et al. 1988; Caviness et al. 1988; Terashima et al. 1992; Lambert de Rouvroit and Goffinet 1998; Tabata and Nakajima 2002; Kikkawa et al. 2003). We specifically wanted to address 1) how is the highly organized laminar and modular architecture of the GRS in the wild-type rodent transformed and 2) is there still evidence of dendrite–dendrite interactions, despite the dispersal of layer 5 pyramidal cells?
As expected, given the laminar dispersal in these mutants, there was no evidence of any micromodularity, which might have been displaced from layer 1. Instead, both in SRK and reeler, immunohistochemistry for OCAM revealed a patch and matrix-like mosaic, where large OCAM– patches in the middle of the cortical thickness were embedded in an OCAM+ matrix. The thalamic and cortical afferents maintained the same relationships to this patch–matrix configuration as in the wild-type rodents (Table 1). Further, by filling neurons with Lucifer yellow (LY) in fixed slices of the reeler GRS, we ascertained that these can be grouped into 2 populations, with dendrites showing preference to either OCAM– patches or the OCAM+ matrix. From in situ hybridization and electron microscopy (EM) results, we conclude that the OCAM+ group corresponded to layer 5 neurons. Thus, even in the disrupted laminar cortex of reeler and SRK, OCAM may exert neuronal population-dependent homophilic or repellent dendritic effects.
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Experimental subjects
The following normal and mutant animals were used for this study: 1) wild-type Wistar rats (>3 months, purchased from Japan SLC, Hamamatsu, Japan), 2) homozygotes for the SRK mutation (SRK/SRK; 5–6 months, generated by pairing Wistar strain heterozygotes at Kobe University School of Medicine), 3) B6C3Fe wild-type mice (>3 months, maintained at Brain Science Institute (BSI), RIKEN, originated from heterozygous B6C3Fe-a/a-rl adults (BSI). The Jackson Laboratory, Bar Harbor, Maine), 4) CB57/6J wild-type mice (purchased from Japan SLC), 5) homozygous reeler mice (>3 months, maintained at BSI, RIKEN, originated from heterozygous B6C3Fe-a/a-rl adults), 6) YFP-H mice (3–4 weeks, Feng et al. 2000; purchased from Jackson Laboratory and maintained at BSI, RIKEN), 7) reeler;YFP-H mutant mice (3 weeks; generated by mating YFP-H mouse with reeler mice and genotyped as previously described by Feng et al. 2000 and D'Arcangelo et al. 1997). All experimental protocols were approved by the Experimental Animal Committee of the RIKEN Institute and were carried out in accordance with the guidelines published in Guide for the care and use of laboratory animals (DHEW Publication No. NIH 85-23, 1996).
Perfusion Fixation
Nembutal (50 mg/kg) was used for anesthetising the following animals: wild-type Wistar rats (n = 5), B6C3Fe (n = 2), and CB57/6J (n = 5) wild-type mice, SRK (n = 4), reeler mice (n = 8), YFP-H mice (n = 3), reeler;YFP-H mutant mice (n = 4). Animals were transcardially perfused, in sequence, with 0.9% saline and 0.5% sodium nitrite for 1 min and 4% paraformaldehyde in 0.1 M phosphate buffer (PB, pH 7.3) for 10 min. Postfixation was performed using the same fixative for 2 h. For Zn histochemistry, we injected sodium sulfide (200 mg/kg) via the vena cava inferior 3 min before saline perfusate. Following fixation, then, the brains were placed in 30% sucrose and, after sinking, were cut into 40-µm-thick sagittal or coronal sections on a freezing microtome.
Single and Double Immunofluorescence for OCAM, VGluT1, and VGluT2
Sections were preincubated for 1 h with 0.1 M phosphate-buffered saline (PBS, pH 7.3) containing 0.5% Triton X-100 and either 5% normal goat serum (PBS-TG) or normal donkey serum (PBS-TD) at room temperature. Serum species were chosen so as to match with the host animal of the secondary antibody. Then, the sections were incubated for 40–48 h at 4 °C in either a mixture of 2 different antibodies or one antibody. The antibodies, raised from different animals in the case of double labeling, were chosen from the following: anti-VGluT1 polyclonal rabbit antibody (SYSY, Gottingen, Germany; 1:1000), anti-VGluT2 polyclonal rabbit antibody (SYSY; 1:1000), anti-VGluT2 polyclonal guinea pig antibody (Chemicon, Temecula, CA; 1:2000), anti-OCAM polyclonal rabbit antibody (Yoshihara et al. 1997; 1:1000), and anti-OCAM polyclonal goat antibody (R&D Systems, Minneapolis, MN; 1:300). Antibody combinations were 1) for OCAM (raised in goat) and either VGluT1 or VGluT2 (raised in rabbit) and 2) for OCAM (raised in rabbit) and VGluT2 (raised in guinea pig). Finally, the sections were incubated for 1.5 h in either PBS-TG or PBS-TD containing the suitable combination of secondary antibodies. These were chosen from the following: Alexa Fluor 488–conjugated anti-rabbit IgG donkey polyclonal antibody (Molecular Probes, Eugene, OR; 1:200); Alexa Fluor 594–conjugated anti-goat IgG donkey polyclonal antibody (Molecular Probes; 1:200); Alexa Fluor 596–conjugated anti-rabbit IgG goat polyclonal antibody (Molecular Probes; 1:200); Alexa Fluor 488–conjugated anti-guinea pig IgG goat polyclonal antibody (Molecular Probes; 1:200).
Double Labeling Combining AChE Histochemistry and Immunofluorescence for VGluT2
AChE histochemistry was performed following Tsuji's (1998) method with slight modification. After washing in a mixture containing 1 ml of 0.1 M citrate buffer (pH 6.2) and 9 ml 0.9% saline (CS), sections were incubated with CS containing 3 mM CuSO4, 0.5 mM K3Fe(CN)6, and 1.8 mM acetylthiocholine iodide for 1 h. After rinsing in PB, sections were intensified in PB containing 0.05% diaminobenzidene (DAB) and 0.03% nickel ammonium sulfate. After washing in PB, we further carried out immunofluorescence for VGluT2 described above.
Double Labeling Combining Zn Histochemistry and Immunofluorescence for VGluT2
For the detection of synaptic zinc, sulphide precipitation (as ZnS) followed by silver amplification was used (Miro-Bernie et al. 2006). Sections were immersed in a solution made of 33% Arabic gum, IntenSE M silver Enhancement kit (Amersham International, Bucks, UK) component A and component B, freshly mixed before use in a 2:1:1 ratio, and developed for 180 min in the dark. Then sections were thoroughly rinsed in PB and in 5% thiosulphate–0.05 M PB for 12 min and processed for immunofluorescence for VGluT2 (described above).
In Situ Hybridization for Mouse OCAM
Polymerase chain reaction (PCR) primers for mouse OCAM (5'-TCACCAAGCAAGATGATGGA-3' and 5'-AAAATTGGTGCCAATCAAGC-3') were designed based on the nucleotide sequence of mouse OCAM (GenBank No. NM_010954 [GenBank] ). The cDNA fragments were obtained by reverse transcriptase–PCR from mouse cDNA. PCR fragments were ligated into the pBluescript II (KS+) vector. The plasmid was linearized with Asp718 or XhoI and used as the template for antisense or sense cRNA probes. The digoxigenin (DIG)–dUTP labeling kit (Roche, Basel, Switzerland) was used for in vitro transcription.
Two wild-type and 2 reeler mice were used for in situ hybridization for OCAM. Animals were perfused as above. Sections were cut (in the coronal plane, at 30 µm thickness) by using a sliding microtome and were washed in PB and postfixed with 4% paraformaldehyde in PB for 10 min. After washing in PB, sections were treated with 1 µg/ml proteinase K for 10 min at 37 °C, acetylated, and then incubated in hybridization buffer containing 0.5–1.0 µg/ml DIG-labeled riboprobes at 60 °C. The sections were sequentially treated for 15 min at 55 °C in 2x standard sodium citrate (SSC)/50% formamide/0.1% N-lauroylsarcosine, twice, for 30 min at 37 °C in RNase buffer (10 mM Tris–HCl, pH 8.0, 1 mM EDTA, 500 mM NaCl) containing 20 µg/ml RNase A (Sigma, St Louis, MO); for 15 min at 37 °C in 2x SSC/0.1% N-lauroylsarcosine, twice; for 15 min at 37 °C in 0.2x SSC/0.1% N-lauroylsarcosine, twice. The hybridized probe was detected by an anti-DIG antibody conjugated with horseradish peroxidase (Roche Diagnostics, Basel, Switzerland; 1:2000 in the blocking buffer) for 2–5 h at room temperature. After washing in TNT (0.1 M Tris–HCl, pH 7.5, 0.15 M NaCl, 0.1% Tween 20) 3 times for 15 min, the sections were treated with 1:50 diluted TSA Plus (dinitrophenol [DNP]) reagents for 30 min according to the manufacturer’s instruction (Perkin-Elmer, Wellesley, MA), and the DIG signals were converted to DNP signals. After washing in TNT 3 times for 10 min, the sections were incubated for 2–5 h at room temperature with an anti-DNP antibody conjugated with Alexa Fluor 488 (Molecular Probes; 1:100) in 1% blocking buffer for the fluorescence detection). Control of hybridization with sense strand-labeled riboprobes showed no hybridization signal. The sections adjacent to those stained for in situ hybridization were also stained for immunofluorescence for OCAM as described above.
Ibotenic Acid Injection into Subiculum of YFP-H Mouse
Three YFP-H mouse (4–5 weeks) were anesthetised with Nembutal (50 mg/kg). In an aseptic surgical procedure, 10 injections of ibotenic acid (10 mg/ml, 0.05 µl each) were made unilaterally in the subiculum by stereotaxic localization (Hof et al. 2000). A 10-µl Hamilton syringe (Reno, NV) with a 32-gauge needle was lowered according to posterior (P), lateral (L), and vertical (V) coordinates in relation to bregma and the skull surface: P, range –3.3 mm to –4.4 mm; L, range 1.6 mm–3.5 mm; and V, range 1.5 mm–4.0 mm. Ibotenic acid solution was delivered over 1 min after a 1 min wait. Five days later, animals were reanesthetized, perfused as described above, and brains were processed for VGluT2 immunofluorescence using Alexa Fluor 594–conjugated secondary antibody (described above).
OCAM Immunoelectron Microscopy
OCAM immunoelectron microscopy was carried out as previously described (Ichinohe et al. 2003). In short, vibratome coronal sections of 50 µm thickness were prepared from 2 of the following animals, wild-type mice and rats, reeler mice and SRK. Perfusion fixation was performed using 4% paraformaldehyde with 0.1% glutaraldehyde in PB with postfixation for 2 h. Tissue including the GRS was trimmed out to facilitate the processing. Sections were incubated in 20% sucrose and then were freeze thawed with liquid nitrogen. Sections were incubated for 1 h with PBS containing 5% normal goat serum (PBS-G) at room temperature and then for 24 h at 4 °C with PBS-G containing rabbit polyclonal anti-OCAM antibody (see above, 1:10 000). After rinsing, signals were visualized with avidin-biotin-peroxidase-complex–DAB method. Sections were osmicated, dehydrated, and flat embedded in resin (Araldite M; TAAB, Aldermaston, UK). From the plastic sections, we further trimmed out both OCAM+ matrix and OCAM– patch, which was easily identified, from mutant rodents, and OCAM+ layer 5 from wild-type rodents. Ultrathin sections were collected on formvar-coated, single-slot grids and examined with an electron microscope (JEM 2000-EX; JEOL, Tokyo, Japan). For quantification, electron micrographs were taken at a magnification of 20 000 from randomly selected fields that included OCAM-labeled elements in the neuropil. Total 100 digital fields were recorded from ultrathin sections (4-µm interval in order to avoid to count the same structures) of one tissue sample from 2 animals of each rodent type examined. On each micrograph, OCAM-labeled profiles were identified based on standard ultrastructural criteria (Peters et al. 1991).
LY Filling of Neurons in Wild-Type and reeler Mice
Four wild-type mice and 5 reeler mice were used. Animals were deeply anesthetized as described above. Brains were removed from the skull and postfixed for 30 min in 4% paraformaldehyde in PB. The 300-µm coronal sections of the GRS were cut by vibratome and mounted onto black Millipore filter papers. The mounted sections were then immersed in a PB solution containing the nuclear dye 4,6-diamidino-phenylindole (DAPI; Sigma), for 1 h. Glass pipettes (1 mm optical density; World Precision Instruments, Sarasota, FL) were pulled on a Brown-Flaming P-97 micropipette puller (Sutter Instrument, Novato, CA). An impedance of 80 M–150 M
was considered optimal for injection. Pipettes were backfilled with 8% LY CH dilithium salt (Sigma) in 0.05 M Tris buffer (pH 7.3). Filled pipettes were lowered toward the tissue chamber by using a micromanipulator (Narishige, Tokyo, Japan). Pipettes were viewed under ultraviolet excitation (355–425 nm), so that both the pipettes and the DAPI-labeled section were visualized together. The pipette tip was coarsely maneuvered using a 4x objective lens (Nikon Optiphot2-UD, Nikon, Tokyo, Japan). Then, with the finer resolution of a 20x objective lens, individual cells were selected and penetrated. Following successful penetration, iontophoresis of LY was achieved by passing a 10-nA positive current for approximately 1 min. Following multiple intracellular injections, the section was immersed in 4% paraformaldehyde in PB for 20 min. The 300-µm-thick sections were then resectioned on a freezing microtome at 50 µm thickness. The thinner sections were preincubated for 1 h with PBS-TD and then were incubated 40–48 h at 4 °C in PBS-TD containing anti-LY polyclonal rabbit antibody (raised by Dr David Pow; 1:40 000), and either anti-VGluT2 polyclonal guinea pig antibody (Chemicon; 1:2000) or anti-OCAM polyclonal goat antibody (R&D Systems; 1:300). Finally, the sections were incubated for 1.5 h in PBS-TD containing Alexa Fluor 488–conjugated anti-rabbit IgG donkey polyclonal antibody (Molecular Probes; 1:200) and either Alexa Fluor 594–conjugated anti-guinea pig IgG donkey polyclonal antibody (Molecular Probes; 1:200) or Alexa Fluor 594–conjugated anti-goat IgG donkey polyclonal antibody (Molecular Probes; 1:200).
Data Analysis
The center-to-center distance of compartments visualized by Nissl staining and immunohistochemistry were measured on digitized images of 20 sections from 2 animals aided by Image J software (http://rsb.info.nih.gov/ij/; National Institutes of Health).
To analyze dendritic organization of LY-filled neurons in relation to patch and matrix compartments, high-resolution images (3900 x 3090 pixels) of LY-filled tissues were taken using a Zeiss Axioskop 2 microscope (Zeiss, Jena, Germany). First, an "overview" of the pattern of OCAM labeling was taken at 100x magnification, and cells randomly selected from successfully injected cells were then analyzed at higher magnification (200x). Depth through the tissue was documented by taking 5 stepwise images (6 µm each step). (Given the well-known shrinkage in the z-dimension, the thickness of 50 µm for microtomed, wet tissue became 30 µm for dehydrated and coverslipped tissue.) These images including LY-filled neurons were then stacked and aligned using Adobe Photoshop (Adobe Systems, San Jose, CA). Using these images, dendrites and cell bodies of the injected neurons were traced with Neurolucida Confocal software (MicroBrightField, Williston, VT). The borders of OCAM+ matrix and OCAM– patches were drawn by the same system. The acquired data were analyzed with NeuroExplorer (MicroBrightField, Williston, VT). We measured the following morphological parameters for each selected neuron: 1) the total length of dendrite in the matrix, 2) the total length of dendrite in the patch, 3) total dendritic length, and 4) the total length of dendrite in the matrix divided by the total dendritic length (M/T ratio). We defined neurons with an M/T ratio below 0.5 as patch-preferring neuron and those with an M/T number greater than 0.5 as matrix-preferring neuron (see Results).
Because the M/T ratio may be strongly influenced by the 3-dimensonal configuration of the surrounding patch and matrix, we have attempted to compensate for this by computer rotation of the reconstructed dendrites while holding constant the position of the cell body, using Adobe Photoshop. Rotation at 90, 180, and 270 degree were carried out against a fixed patch–matrix configuration (Fig. S1), and the M/T ratio was recalculated for these 3 conditions. If dendrites of a neuron have preference to matrix, the M/T ratio of 0 degree position (original position) for this neuron should be high compared with the 3 rotated positions (90, 180, 270 degree), and vice versa. Statistical comparison between original position versus the 3 rotated positions was performed separately for groups of patch and matrix preference neurons using the Kruskal–Wallis test (P < 0.05).
Light microscopic photographs were taken on digital cameras (Axioscop2 and Axiocam, Carl Zeiss Vision, München-Hallbergmoos, Germany). Size, brightness, and contrast of images were adjusted to coincide with the real image, by using Photoshop software (Adobe Systems).
The Nomenclature
Areal, laminar, and nuclear boundaries were defined by using thionin for cell bodies, VGluT2 immunohistochemistry, or AchE histochemistry. The nomenclature and abbreviations for cortical areas follow Paxinos and Watson (2004) for rats and Hof et al. (2000) for mice. For zinc-positive structures, we use the abbreviation Zn+ (no superscript, so as not to confuse with Zn2+).
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Cytoarchitecture of Wild-Type and Mutant Rodents
The GRS of the wild-type rodent shows a clear laminar organization (Fig. 1A,C). In the wild-type rat, the GRS has a thick infragranular stratum (layers 5 and 6), with distinct large pyramidal neurons in layer 5; a thin, cell-sparse layer 4; thin, but clearly distinguishable layers 2 and 3; and a relatively thick layer 1. Small, densely packed pyramidal neurons aggregate in layer 2. The laminar organization of wild-type mouse GRS is basically similar, except that the cell sparse layer 4 is harder to distinguish and the overall cortical thickness (about 1.0 mm) is about half that of rat GRS (about 2.0 mm).
In the GRS of both reeler and SRK, the laminar structure is conspicuously disrupted (Fig. 1B,D). In the position of layer 1, defined by its subpial location, there is a more cell-dense stratum, presumably, corresponding to layer 6. This is consistent with the quasi-inverted disruption of the cortical organization, as described in the literature (Aoki et al. 2002; Yamamoto et al. 2003). Large cell bodies, likely to correspond to layer 5 pyramids of the wild-type phenotype, are scattered throughout the cortical thickness. Aggregations of mainly small cells are apparent in the mid-cortical thickness. These aggregations are elongated in the pial to white matter plane, with a center-to-center distance (measured parallel to the pia) of 50–150 µm in SRK and 40–100 µm in reeler mouse.
Organization of OCAM and Input-Specific Markers in the GRS of Wild-Type and Mutant Rodents
In the wild-type rat and mouse, OCAM immunoreactivity is bistratified, with 2 dense bands, one in layer 1 (especially 1b, c) and another in layers 5 and 6 (Fig. 2A,D and Table 1). In wild-type rat, the superficial band (layer 1b,c) has a distinct notch-like appearance (Fig. 2A), but this is not evident in the mouse (Fig. 2D). (Dendritic bundling, as assayed by MAP2, is not obvious in the adult mouse but can be discerned at P8 mice in which the Escherichia coli lacZ gene is integrated into the neurotrophin-3 locus, see Fig. 1F in Vigers et al. 2000.) Double labeling for OCAM and VGluT2 (presumptive thalamocortical terminals; Fujiyama et al. 2001) showed that the expression patterns of OCAM and VGluT2 are generally complementary, except for layer 2, which is devoid of both molecules (Fig. 2A–C and Table 1). In contrast, double labeling for OCAM and VGluT1 (presumptive corticocortical terminals; Fujiyama et al. 2001) showed colocalization, again except for layer 2, which is devoid of both molecules (Fig. 3A–D and Table 1). From these results, we conclude that, in wild-type rodent GRS, VGluT2+ thalamocortical and VGluT1+ corticocortical terminals have preferential distributions and that these are strongly associated with OCAM distribution (see also: Wyss et al. 1990; Kaneko et al. 2002; Ichinohe et al. 2003; Miro-Bernie et al. 2006).
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In both reeler and SRK, OCAM immunohistochemistry showed a distinctly different configuration from the GRS of wild-type rodents. Instead of a laminar pattern, OCAM– patches appeared within an OCAM+ matrix. The OCAM+ matrix was localized to the outer (pial) and inner (white matter) cortical zones, and surrounded OCAM– patches, which were situated in the middle of the cortical thickness (Figs 2E,H,I,L and 3E,H). This is the same middle zone that contains small cell aggregations (Fig. 1B,D); and alternate sections for Nissl and OCAM show that the cell aggregations correspond with the OCAM– patches (data not shown). The aggregations and patches are comparable in shape and size, with a center-to-center distance of 50–150 µm in SRK and 40–100 µm in reeler mouse.
In both reeler and SRK, double labeling for OCAM and either VGluT1 or VGluT2 showed an orderly relationship; namely, OCAM– patches matched with patches that are VGluT2+ (Fig. 2E–L) and VGluT1– (Fig. 3E–H). Thus, although the normal lamination was disrupted in the mutant rodents, VGluT2 and VGluT1 have the same complementary relationship as in the wild type and the same association with OCAM (Table 1).
To confirm the complementary relationship of VGluT1 and VGluT2, we further tested with AChE histochemistry, known to correspond to thalamocortical terminations from the anterior thalamic nuclei (Vogt 1985) and with Zn histochemistry, known to correspond to a subpopulation of corticocortical terminations (Garrett et al. 1992; Casanovas-Aguilar et al. 1998; see also Fig. 4E–G). As expected, double labeling with VGluT2 resulted in a match with AChE (Fig. 4A,B), but an interdigitation with Zn in the mutants (Fig. 4C,D), as in the wild-type rodents (Fig. 4E–G and Table 1).
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Reeler; YFP-H Mutant Mouse: Subiculoretrosplenial Projections form Patches
In addition to thalamic and cortical inputs, a third major input to the GRS is from the subiculum (Vogt 1985, van Groen and Wyss 2003). To determine how this input reorganizes in the mutant GRS, we compared subicular GRS projections in reeler and in the wild-type YFP-H transgenic mouse, where YFP is expressed in some neurons under the control of the promotor/enhancer of Thy-1 gene (Feng et al. 2000). In the GRS of the YFP-H mouse, YFP+ axons form a dense band in layers 3 and 4 (Fig. 5A–C and Table 1). These are thalamorecipient layers, as shown by VGluT2-ir, but also receive dense subicular input (Vogt 1985; Van Groen and Wyss 2003). To identify the source of the YFP+ axons, we injected ibotenic acid into the ipsilateral subiculum. Subsequent to this, the dense axon band disappeared unilateral to the lesion. There was no obvious change either in the layer 5 axonal plexus or VGluT2-ir (Fig. 5D–F); but YFP labeling in layer 1b,c is also diminished. These results suggest that the YFP+ axons in layers 3 and 4 as well as those in 1b,c are mainly of subicular origin. Consistent with this conclusion, in the YFP-H mouse, the thalamic nuclei projecting to the GRS (i.e., AV, AD and LD, Van Groen and Wyss 2003) have very few YFP-expressing neurons, whereas most of the pyramidal neurons in the subiculum strongly express YFP (not shown).
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In reeler;YFP-H mutant mouse, YFP axons formed patches in the GRS (Fig. 5G–L). These have the same appearance and size as patches positive for VGluT2 and negative for OCAM in the reeler. From the results in wild-type YFP-H mouse after ibotenic acid injections, these axons are likely to originate from the subiculum in the mutant as well (Table 1).
Generality of Patch–Matrix-like Organization in Other Cortical Areas of Mutant Rodents
Although this investigation is concentrated on the GRS, OCAM immunohistochemistry revealed a patch and matrix configuration widely throughout the cerebral hemisphere in visual, auditory, barrel, perirhinal, and anterior cingulate cortical areas (Fig. 6). The expression level tended to be lower than that in the GRS, and there was some area-specific variability in the shape of the patch compartments and their position within the cortical thickness. Further detail and additional results will be described in a separate communication (Wintzer M, Ichinohe N, Yoshihara Y, Ogawa M and Rockland KS, in preparation).
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Postsynaptic Localization of OCAM-ir in Wild-Type and Mutant Rodent GRS
In a previous EM study of layers 1–4 of wild-type rat GRS, we reported that OCAM-ir structures are largely dendritic and that these originate from layer 5 neurons (Ichinohe et al. 2003). To establish the identity in mutant rodent, we first compared in situ hybridization in wild type and mutant. OCAM mRNA in GRS of wild-type mouse was strongly expressed in layer 5 neurons as expected, with moderate expression as well in layer 6, but no signal was apparent in supragranular neurons (Fig. 7A and Table 1). In the reeler GRS, OCAM mRNA expression was found throughout the cortical thickness. This is consistent with previous descriptions that connectionally defined layer 5 pyramidal neurons are radially scattered (Fig. 7B; Terashima et al. 1983; Hoffarth et al. 1995; Polleux et al. 1998; Baba et al. 2007). In the immediate subpial zone, presumed to correspond mainly to an inverted layer 6 (Aoki et al. 2002; Yamamoto et al. 2003), many neurons expressed OCAM mRNA. Deeper, patch-like areas (arrows in Fig. 7C) contained fewer OCAM mRNA expressing neurons, and by comparison with an adjacent section, stained for OCAM protein, these patches could be ascertained to match with OCAM– patches (arrows in Fig. 7C,D, Table 1). From these results, we conclude that OCAM-ir dendrites in reeler GRS likely originate from displaced layer 5 pyramidal neurons.
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Next, we carried out EM investigations of OCAM-ir structures in the mutant rodents. As expected, in both reeler mice and SRK, the majority of OCAM-ir structures (in OCAM+ matrix) were dendritic. These could be identified as spines and small-caliber dendrites (<1 µm; about 90% of all OCAM-ir structures) as well as large caliber dendrites (>1 µm; about 10% of all OCAM-ir structures). OCAM-ir somata were evident, but OCAM+ axons or synapses were rare, as in the wild type (<1% of profiles examined). For somata, the external cell membrane and endoplasmic reticulum were immunoreactive (Fig. 8A,B). OCAM-ir dendrites can frequently be seen in direct dendrite–dendrite apposition and sometimes in soma-dendritic apposition. However, there was neither indication of junctional specializations (e.g., gap junctions) (Fig. 8A,C–E) nor of simultaneously labeled pre- and postsynaptic elements. Similar results were obtained from layer 5 of the wild-type rodents (data not shown; for layers 1–4 see also Ichinohe et al. 2003
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In samples from an OCAM– patch, we could find some OCAM-ir somata and dendrites (data not shown), as predictable from the in situ hybridization data (Table 1). However, OCAM-ir structures were considerably fewer than in the OCAM+ matrix, consistent with light microscopic observations. The level of OCAM-ir is presumed to correlate with the degree of dendritic branching of OCAM+ layer 5 neurons. In wild-type rodents, apical dendrites passing through layer 2–4 in wild-type rodents appear as OCAM+ profiles (see Fig. 5 in Ichinohe et al. 2003
). Subpopulations of layer 5 neurons with abundant branches in OCAM– layers 2–4 (see Fig. 5 in Wyss et al. 1990) are assumed to be OCAM–. Dendritic Arbors Prefer Specific OCAM Compartments
Our next question was whether the malpositioned dendrites in reeler and SRK would have any orderly relationship to the OCAM-delineated patch or matrix. We addressed this issue by visualizing single dendritic arbors (filled by LY injection in fixed slice) in relation to OCAM-ir. The results were compared between wild-type and reeler mice.
In wild-type mice, we filled and reconstructed 7 neurons in layers 2 and upper 3 and 11 neurons in layer 5. Six of the 7 supragranular neurons clearly elaborated dendrites in OCAM– layers (i.e., layers 1a and 2–4, Fig. 9A,B). That is, apical dendrites of these supragranular neurons branched extensively in layer 1a (OCAM–), but not layer 1b, c; and their basal dendrites rarely entered layer 1b, c or layer 5 (OCAM+). In contrast, all the 11 infragranular neurons elaborated dendrites in OCAM+ layers (i.e., layer 1b,c and layer 5; Fig. 9C). Some of their basal and oblique dendrites ascended upward toward the pia but rarely invaded layer 4 (OCAM–).
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In reeler, large layer 5 neurons (putative OCAM+) are dispersed, and their normal dendritic orientation is in general lost (Terashima et al. 1992
). Despite these anomalies, we were able to ascertain a strong tendency for either dendritic preference or avoidance of specific OCAM compartments. Of 17 neurons filled and reconstructed, 10 arbors were preferentially within the OCAM+ matrix and 7 were preferentially within the OCAM– patch (Fig. 10). Of the 10 neurons with dendrites preferring the OCAM+ matrix, for 8 the somata were also within the OCAM+ matrix (Table 2). The 2 other neurons are likely to be displaced layer 5 cells (see in situ hybiridization for OCAM, Fig. 7).
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For the sake of an objective classification, we calculated a ratio to express the length of dendrite in the matrix compartment in relation to total dendritic length (matrix/total dendritic length or "M/T ratio," Table 2). An M/T histogram (Fig. 11A), based on reconstructions of the 17 filled neurons, reveals 2 groups, i.e., one is below 0.2 and the other is above 0.5. We defined neurons with a number below 0.5 as patch-preferring neuron (n = 7) and those with an M/T number greater than 0.5 as matrix-preferring neuron (n = 10; Table 2 dotted line). The resultant grouping agrees with the more qualitative classifications described above.
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Because the length of dendrite within a patch may be strongly influenced by the 3-dimensional configuration of the surrounding patch and matrix, we have attempted to compensate for this by computer rotation of the reconstructed dendrites while holding constant the position of the cell body. The 90-, 180-, and 270-degree rotations were carried out against a fixed patch–matrix configuration (Fig. S1), and the M/T ratio was recalculated for these 3 conditions (Table 2 and Fig. 11B,C). The 0 degree position (original position: blue column) is obviously skewed to either a low or high M/T number compared with the 3 rotated positions (90, 180, 270 degree: red column in Fig. 11B for patch-preferring neurons and green column in Fig. 11C for matrix-preferring neurons). The Kruskal–Wallis test shows that this deviation is statistically significant (P < 0.001 for patch-preferring neurons and P < 0.025 for matrix-preferring neurons). This supports our interpretation that the position of the cell body is less important than the active preference of dendrites for either patch or matrix domain.
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In the GRS of wild-type rodents, thalamocortical (VGluT2) and corticocortical (VGluT1) inputs are highly stratified, with a complementary relationship to each other. Layers 1a, 3, and 4 are positive for VGluT2 and layers 1b,c and 5 are positive for VGluT1. In layer 1b, the 2 systems form a small-scale modular organization in relation to apical dendrites of layer 2 neurons (colocalized with VGluT2) and distal tufts of layer 5 neurons (colocalized with VGluT1). This organization is also discernible with immunohistochemistry for OCAM, a cell adhesion molecule associated mainly with dendrites of layer 5 neurons, where OCAM-ir corresponds to corticocortical layers and modules.
In this study, the use of OCAM as reference marker revealed a distinct patch and matrix configuration in the GRS of both reeler and SRK mutants, where thalamocortical and corticocortical inputs maintain the same complementary relationship as in the wild-type rodents (corresponding to OCAM- patches and an OCAM+ matrix, respectively). The patch and matrix mosaic is particularly evident in the GRS, but a recognizably similar organization can be discerned widely throughout the cortex (Fig. 6; Wintzer M, Ichinohe N, Yoshihara Y, Ogawa M and Rockland KS, in preparation).
Segregation of inputs, by modules or layers, is a basic cortical feature, and modular segregation occurs as well in other structures, such as the superior colliculus (Mana and Chevalier 2001) and striatum (Joel and Weiner 2001). In some areas, notably the primary sensory, input segregation is associated with parallel submodality (e.g., rodent barrel cortex, Chmielowska et al. 1989; monkey visual cortex; Casagrande and Kaas 1994). In the nigrocollicular pathway, modularity is proposed as working to select motor programs for different classes of orienting behavior (Mana and Chevalier 2001). In the GRS, the coincidence of subicular and thalamocortical inputs suggests a convergence and interaction of place (subicular) and head-direction (thalamic) properties (Smith and Mizumori 2006; Taube 2007). A specialized cell type, head-direction–dependent place cell, so far unique to the GRS, may require combination of these inputs (Cho and Sharp 2001).
Early investigations of thalamocortical terminations to sensory cortex show an elongated patchy distribution (Caviness and Frost 1983), reminiscent of the VGluT2+/OCAM– patches in our material. Dispersed thalamocortical aggregates can also be detected by cytochrome oxidase in reeler and SRK somatosensory cortex (for reeler, Fig. 4 in Strazielle et al. 2006; for SRK, Higashi et al. 2005).
One previous study of reeler mouse demonstrated a striking mosaic of AChE+ and AChE– zones (Steindler et al. 1994), which seems identical to our results. In that study, the mosaic was assigned to visual cortex; but in retrospect, it may actually have been in the GRS. That is, in our material, the density of AChE activity abruptly declines at the lateral edge of GRS (see Fig. 4B).
So far, there has been little evidence from retrograde labeling experiments in other areas of any patch–matrix organization. Corticothalamically projecting neurons are displaced superficially in a band-like pattern (Aoki et al. 2002; Yamamoto et al. 2003). Callosally projecting neurons are abnormally biased to the deeper two-thirds (Caviness and Yorke 1976; Terashima et al. 1985; Aoki et al. 2002). Layer 5 corticospinal neurons are abnormally biased to the upper cortical stratum but are more precisely described as radially scattered (motor cortex, Terashima et al. 1983; Hoffarth et al. 1995; Polleux et al. 1998; sensory-motor cortex, Ikeda and Terashima 1997; areas 3 and 6, Polleux et al. 1998). Similarly, layer 5 corticotectal neurons in the visual cortex are widely scattered from the white matter to the pial surface (Baba et al. 2007). However, in one report, where young reeler mice received injections to visualize corticobrainstem, corticospinal, and corticothalamic neurons in somatic sensorimotor cortex (injection: P2; perfusion: P5), there is some indication of cell-sparse patches (OCAM–?) in the middle of a cell-filled "matrix" (Fig. 1 in Hoffarth et al. 1995). The apparent absence of conspicuous patchiness of projection neurons most likely can be attributed to differences in dendritic versus soma location.
Dendrite–Dendrite Interaction and a Role for OCAM
We are proposing that the patch–matrix mosaic results in part from dendrite–dendrite interactions, where the OCAM+ dendrites of a subgroup of layer 5 neurons (see Postsynaptic Localization of OCAM-ir in Wild-type and Mutant Rodent GRS) aggregate to form the matrix compartment by homophilic interactions and influence patch formation by heterophilic repulsion. This is the mechanism proposed for the formation of dendritic modules in the uppermost layers in the wild-type rat (Ichinohe et al. 2003). In support of this proposal, in situ hybridization in the mutant rodents revealed that neurons that highly express OCAM mRNA (putative layer 5 neurons) tend to avoid OCAM– patches. In addition, dendritic arbors, visualized by filling with LY, appear to selectively sample from compartments that are OCAM– (dendrites of layer 2 neurons) or OCAM+ (dendrites of layer 5 neurons; Fig. 9).
Clearly, the establishment of lamination (wild type) or compartments (mutants) involves multiple mechanisms. At early stages (E15–E17), afferent systems (i.e., monoaminergic fibers) have been proposed as an important determinant of the direction of dendritic growth (Pinto Lord and Caviness 1979), and in barrel cortex, the influence of thalamocortical connections on dendritic orientation of stellate cell is well established (Harris and Woolsey 1979; Steffen and Van der Loos 1980; Datwani et al. 2002). Our proposal, that dendrite–dendrite interactions are another important factor at the early postnatal stages, might be further investigated by selective lesioning of the thalamocortical or other inputs (for serotonergic inputs and presubiculum, see Janusonis et al. 2004), with the prediction that the basic patch–matrix will persist.
In layer 1 of the wild-type GRS, modularity is apparent with dendritic markers from as early as P3 by OCAM (or P5 by GluR2/3; Ichinohe et al. 2003), but according to Ma et al. (2002), thalamocortical axons have just reached the subplate of the GRS at P3. If additional experiments confirmed a similar early time course of OCAM expression in the reeler and SRK, this would provide further support for an instructive role for dendrites in the formation of the patch–matrix mosaic. The time of arrival for subicular afferents is not known.
Both dendrite–dendrite and dendrite–axon interactions have been extensively investigated in the context of dendritic field formation, maintenance, and remodeling and are well known to involve multiple cellular and molecular mechanisms (Datwani et al. 2002; Wong and Ghosh 2002; Lardi-Studler and Fritschy 2007; Parrish et al. 2007). Undoubtedly, therefore, the proposed homophilic–heterophilic dendritic influences of OCAM in the GRS are one of multiple signaling mechanisms.
The role of OCAM has been intensively investigated in the olfactory system of mice (Alenius and Bohm 1997; von Campenhausen et al. 1997; Yoshihara et al. 1997; Nagao et al. 2000; Treloar et al. 2003; Hamlin et al. 2004; Walz et al. 2006). It is known to be expressed in axons of a subset of sensory neurons in the ventral olfactory epithelium (which target OCAM– dendrites) and in dendrites of dorsally located neurons in the olfactory bulb (which receive OCAM– axons; Treloar et al. 2003). These complementary expressions have recently been implicated in the intraglomerular compartmentalization, which is disrupted in OCAM-deficient mice (Walz et al. 2006). In the GRS, there is a preponderant association of OCAM with postsynaptic dendrites, not axons, which is why we have proposed a mechanism of population-dependent dendritic attraction or repulsion (Ichinohe et al. 2003; this study). It seems clear that OCAM can influence modular formation in a range of different environments (wild-type GRS, mutant GRS, and olfactory bulb).
In summary, we have demonstrated a patch–matrix mosaic in the reeler mutants and proposed that this is in part based on segregation of specific inputs in relation to subpopulations of dendrites. Similar methods, using OCAM, VGluT1, and VGluT2 as a reference markers, may be applicable for investigating input–target relationships in transgenic mice with defects in cellular migration and positioning, morphology of pyramidal cell dendrites, or afferent ingrowth (e.g., cGMP-dependent protein kinase I knockout mouse, doublecortin knockout mouse, Cdk5 knockout mouse—Demyanenko et al. 2005; Deuel et al. 2006; Ohshima et al. 2007).
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Supplementary Fig. S1 can be found at: http://www.cercor.oxfordjournals.org/.
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Funding |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionSupplementary MaterialFundingReferences |
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Brain Science Institute, RIKEN; by Grant-in-Aid for Scientific Research on Priority Areas Molecular Brain Science/System study on higher-order brain functions from the Ministry of Education, Culture, Sports Science and Technology of Japan (grant number, 17024064; 18020032; 18500270); the Joint Research Programs of the National Institute for Basic Biology, Japan; the National Institute for Physiological Science, Japan.
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Acknowledgments |
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We thank Ms Yoshiko Abe and Hiromi Mashiko for excellent technical assistance, Ms Hiroko Katsuno for elegant electron microscopic work, and Dr Hiroyuki Nakahara for helpful comments on statistic analysis. We are grateful to Dr T. Hashikawa (RIKEN, BSI) and members of his laboratory and Dr Y. Kubota (National Institute for Physiological Science) for general EM support and advice. Conflict of Interest: None declared.
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