1 Dyslexia Research Laboratory and Charles A. Dana Research Institute, Beth Israel Deaconess Medical Center; Division of Behavioral Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215 and , 2 Program of Neuroscience Harvard Medical School, Boston, MA 02115, USA
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Abstract |
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Introduction |
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There are changes in thalamic neuronal size in humans and rodents with cortical anomalies of this type (Livingstone et al., 1991; Galaburda et al., 1994
; Sherman et al., 1995
;Jenner et al., 1996
; Herman et al., 1997
) that may also result from altered connectivity. We have hypothesized that the thalamic cell changes and connectional abnormalities associated with the ectopic neurons may relate to the learning difficulties seen in these mice (Denenberg et al., 1991a
,b
, 1992
; Schrott et al., 1992
, 1993
; Boehm et al., 1996a
,b
; Waters et al., 1997
) and in individuals with dyslexia. A critical step for supporting this view is to determine whether ectopic neurons are connected substantially with other cortical areas and with the thalamus. Preliminary findings showed that an antibody directed against the 68 kDa component of neurofilament protein revealed tightly packed, radially oriented fiber bundles within ectopias and in the underlying cortical layers (Sherman et al., 1990
). Fibers from the bundles were also seen extending into the corpus callosum. The unusual organization of these fibers within the cortex, which were never present in mice without ectopias, indicated that the misplaced neurons might be aberrantly connected. It has not been determined, however, what are the specific targets of the neurofilament-labeled fibers, or whether the fibers originate from or terminate on the ectopic neurons. Therefore the tracers DiI (1,1'-dioctadecyl- 3,3,3',3'-tetramethylindo-carbo- cyanine perchlorate) and BDA (biotin dextran amine) were used in the present study to determine whether, as expected, the ectopic neurons were connected abnormally to ipsilateral and contralateral cortices, as well as to thalamic nuclei.
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Materials and Methods |
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All mice were obtained from The Jackson Laboratories (Bar Harbor, ME). Seven adult NXSM-D (two female, five male) and four adult NZB/BINJ (one female, three male) fixed brains (see below) with single ectopias visible on the surface were used for the DiI studies. Ten ectopias were located in the primary somatosensory cortex (Par1) (Zilles, 1985), of which four showed incomplete diffusion of DiI. One ectopia was in the forelimb somatomotor cortex (FL). A separate group of adult NZB mice received small injections of BDA into the thalamus. Five mice from this group had both large ectopias in Par1 and accurate injections into the ventrobasal complex (VB). The remaining mice without ectopias were used for comparison purposes. Over 40 NXSM-D and NZB/BINJ brains without ectopias had DiI placed just under the pial surface in layer I of the homologous cortex. An additional 100 mice without ectopias were injected with BDA, from which animals with injection sites comparable to those in the experimental group were chosen for comparison.
DiI
DiI is a brightly fluorescent carbocyanine dye that diffuses in both the anterograde and retrograde directions labeling both afferent and efferent fibers from the site of DiI placement in either fixed or living tissue (Elberger and Honig, 1990; Haugland, 1996
). Mice were anesthetized and transcardially perfused with 0.9% saline for one min followed by 2% paraformaldehyde/0.1% glutaraldehyde. The brains were removed and stored in this fixative. After several days the outside surface of the brain was lightly stained by immersion in a methyl-green/alcian blue solution. The brains were examined under a dissecting microscope to locate ectopias. Large ectopias (~300 µm in diameter) appeared as slightly raised small round protrusions on the surface of the brain.
Using a glass micropipette with a diameter of 1020 µm, a small crystal (~10 µm in diameter) of DiI (Molecular Probes, Eugene, OR) was placed just under the pial surface onto the middle of the visualized ectopias. The DiI crystal usually was confined to layers III. In mice without ectopias a small crystal of DiI was placed just below the pial surface into the cortical areas that matched the location of ectopias in other brains. The brains were stored in fixative at 37°C for up to 4 months. The fixative was changed every 34 weeks.
The brains were cut with a Vibratome into 100 µm coronal sections and mounted on subbed slides. Most of the sections were viewed uncoverslipped with a Zeiss Axiophot microscope equipped with a rhodamine filter set (Zeiss set 15: BP 546, FT 580, LP 590) for viewing the orangered DiI fluorescence. The remaining slides were coverslipped using a glycerol coverslip medium that contained 5% n-propylgallate to reduce photobleaching (Giloh and Sedat, 1982). Some sections were counterstained with m-phenylenediamine (m-PhD) so that cell bodies could be visualized (Quinn and Weder, 1988
). This yellowgreen fluorescent counterstain, which is illuminated using a FITI fluorescent filter set (Omega xF22: BP 485, FT 505, LP 530) allowed us to confirm that the DiI was accurately placed in ectopias and to identify the location of both thalamic and cortical connections.
BDA
Because of the fluorescent properties of DiI it is difficult to distinguish afferent and efferent connections as individual labeled cell bodies could not be visualized, therefore BDA was used to further character- ize the connections between somatosensory cortical ectopias and the ventrobasal complex of the thalamus. BDA is a high molecular weight hydrophilic polysaccharide which in living tissue is actively transported in both the retrograde and anterograde directions (Haugland, 1996). BDA fills somas, dendritic arbors and synaptic terminals, giving labeled cells a Golgi-like appearance (Rajakumar et al., 1993
).
Mice were anesthetized with an i.p. injection of Avertin (0.02 cc/g) and placed in a stereotaxic apparatus. BDA (10 kDa; Molecular Probes, Eugene, OR) was dissolved in distilled water (concentration of 10%) and was pressure injected using a glass micropipette (diameter 1020 µm) attached to a Pneumatic PicoPump (World Precision Instruments, Inc., Sarasota, FL). With the force of two to three puffs of air at 20 psi for 5 ms, small amounts of BDA were injected bilaterally (to increase the likelihood of an ectopia being present) into the VB of the thalamus. The injection site, defined as that area where all cells were intensely and uniformly stained, varied in diameter between 350 and 550 µm (see Figure 1). In most animals, the injection site was centered in the caudal part of the VB and included both the ventral posteromedial (VPM) and ventral posterolateral (VPL) thalamic nuclei. Larger injections sometimes in- cluded the lateral part of the posterior thalamic nuclear group (Po) and/or the medial part of reticular thalamic nucleus (Rt). The coordinates from the Franklin and Paxinos atlas (Franklin and Paxinos, 1997
) were not accurate for NZB mice. Although the bregmalambda distance measured by Franklin and Paxinos in C57BL/J6 mice (4.21 ± 0.51 mm) was similar in the NZB mice (45 mm), intersections of the lambdoid and bregma sutures through the sagittal suture were shifted caudally in NZB mice. In order to accommodate this shift the coordinates were set at AP 1.1, ML ±1.8 from the bregma and 3.2 from the dura.
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In some mice, double labeling using an antibody (SMI-311 from Sternberger Monoclonal Inc., Lutheville, MD) directed against neuro- filaments was performed to verify that a fiber bundle was present underlying an ectopia. The brain tissue was incubated overnight in the primary antibody at 4°C in a 1/1000 dilution. The vehicle (diluent) for all incubations was 5% rabbit serum in PBS. The sections were placed into a solution containing the linking antibody (rabbit anti-mouse immuno- globulin; Dakopatts Z259 dilution 1/50) at room temperature for 2 h. The sections were exposed to a 1/250 dilution of mouse PAP (Dakopatts B650). The tissue was pre-incubated in a benzidine dihydrochloride (BDHC) solution without hydrogen peroxide for 10 min. The reaction was then carried out on ice to reduce background staining in freshly prepared BDHC solution which contained 0.005% hydrogen peroxide. The tissue was processed for BDA as above except that non-nickel- enhanced DAB was used so that the DAB would not develop too darkly and obscure the other label.
Adjacent sections of tissue were processed using the neuronal nuclei antibody (NeuN) which specifically labels neuron-specific nuclear protein, to confirm that the BDA-labeled cell bodies in the ectopias were neurons (Mullen et al., 1992). The NeuN antibody protocol was the same as that described for the double labeling of neurofilament and BDA described above. The tissue was incubated overnight at 4°C in a 1/500 dilution NeuN antibody (Chemicon International Inc. Temecula, CA). The vehicle (diluent) for all incubations was 5% horse serum in PBS. The linking antibody for NeuN was a horse anti-mouse immunoglobulin.
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Results |
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Despite the lack of contralateral corticocortical connec- tions to and from ectopias, DiI placed onto ectopias did show the presence of ipsilateral corticocortical connections. For instance, labeled cell bodies and fiber terminals were seen in the supra- granular layers of the ipsilateral primary motor cortex (Fr1) (Figure 6A,B). In addition, fibers, but no retrogradely labeled cell bodies, were seen in the supragranular layers of lateral parts of Par1and the secondary somatosensory cortex (Par2) (Figure 6C,D
). Although a similar pattern of staining was seen in normal mice, the intensity of the labeling was reduced in both the motor and somatosensory cortices.
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Discussion |
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In NZB and NXSM-D mice with molecular layer ectopias, however, the organization of the connections of the somatosens- ory cortex was unusual. First, as visualized with neurofilament antibodies (Sherman et al., 1990), there was a dense, radially oriented bundle of fibers underlying the ectopias which BDA labeling revealed contained both afferent and efferent fibers. It appeared as if this bundle resulted from a bottleneck at the lower edge of the ectopias. Electron microscopic analyses of cortical ectopias have revealed thin pericyte septae encircling the ec- topias (Boehm et al., 1995
). These septae may act as a boundary separating ectopias from the adjacent cortex, restricting the path by which fibers enter and exit the ectopias. Thus bundles appear to be an important characteristic of the anatomical organization of cortex that contains an ectopia. Additionally, the confinement of the BDA-labeled fibers to the ectopias also suggests that this boundary prevents the labeled fibers from extending into the surrounding cortex and may be responsible for reducing the lateral spread of DiI placed into an ectopia, resulting in a cone of intensive labeling and less lateral spread of the DiI than seen in non-ectopic cortex.
We thought that the bundles, although resulting from structural alterations at the site of ectopias, were accompanied by a more widespread disorganization of the connectional archi- tecture; therefore, we examined the termination and origin- ation of the fibers in these bundles. Fibers in the bundles were connected both cortically and subcortically. Axons originating in the ectopias that extended subcortically could be visualized in the internal capsule and thalamus, where they connected with nuclei Rt, VB and Po. No other thalamic nuclei were labeled. The locations of these connections correspond to those seen in mice without ectopias but with different intensity of staining. In mice with ectopias staining was more robust in VB, with only light staining seen in Po. In mice without ectopias this pattern was reversed, with greater staining in Po than in VB. This shift in intensity may be due to the heterogeneous population of neurons in ectopias. Birthdating studies have shown that ectopias consist of neurons from all cortical layers (Sherman et al., 1992). Normally the thalamocortical projections from VB terminate in layer IV, whereas the majority of corticothalamic projections originate from layer VI of the somatosensory cortex (Emmers, 1988
; Armstrong-James and Callahan, 1991
; Armstrong-James et al., 1991
; Diamond et al., 1991
, 1992
). Displaced layer IV and VI neurons in ectopias may be responsible for the robust staining in VB. In normal cortex these neurons are not labeled by the superficial placement of DiI, which only labels layer I. Layer I has been shown to have numerous connections with Po and sparse connections with VB (Armstrong-James and Callahan, 1991
; Armstrong-James et al., 1991
; Diamond et al., 1991
, 1992
; Guillery, 1995
; Sherman and Guillery, 1996
). This pattern of connections, which was confirmed by the BDA injections into VB, would result in the robust staining in Po and light staining in VB visualized in mice without ectopias. Further, the reduction of Po labeling from the ectopias may reflect the lack of DiI spread outside the ectopia, which would result in less layer I labeling. Further studies combining birthdating and tracers must be done to confirm this hypothesis
Analysis of the cortical connectivity of the ectopias revealed labeled fibers from ectopias to ipsilateral cortical areas. Both retrograde and anterograde labeling were seen ipsilaterally in Fr1 and anterograde labeling was seen in lateral parts of Par1 and Par2. Like the thalamus, the ipsilateral cortical connections from ectopias do not differ in location, but rather in intensity from those connections seen in non-ectopic cortex;in normal cortex staining was not as dense as that seen in mice with ectopias.
This intensity difference, like that in the thalamus, may also reflect the heterogeneous population of neurons labeled within the ectopias. Corticocortical projections normally originate from layers II/III and V (Killackey et al., 1989; Koralek et al., 1990
; Catalano et al., 1991
). Typically, only those neurons in the upper part of layer II would be labeled with DiI, labeling only a small proportion of the neurons responsible for these connections. However, when DiI is placed within the heterogeneous cells of the ectopias it might label a greater proportion of the ipsilateral connections, resulting in greater staining. With this argument in mind one could hypothesize that contralateral connections should be greater from ectopias than normal cortex; however, the opposite result was obtained.
DiI-labeled fibers from the bundles were seen in the corpus callosum and appeared to cross into the opposite hemisphere. There was no evidence, however, that they were connected with neurons in the contralateral cortex. This differed from the clear contralateral connections seen in the cortex of mice without ectopias. This could not be explained by diffusion distance or time. The distance to labeled thalamic targets was as great as the distance to non-labeled contralateral cortical targets, and there was no lack of contralateral cortical labeling in controls after the same diffusion time. The most likely explanation for the lack of clear contralateral staining in mice with ectopias is that the contralateral cortical connections were greatly reduced and so diffuse that they could not be seen above the background fluorescence.
Similar populations of neurons in layers II/III and V give rise to both the contralateral and ipsilateral cortical connections. The present results suggest a reduction in the former and an increase in the latter. It is plausible that neurons from these cortical layers, when displaced to the ectopias, connect ipsilaterally rather than contralaterally. Because there is competition for cortical targets between thalamic and transcallosal neurons (Ivy et al., 1979; Ivy and Killackey, 1981
; Innocenti and Clarke, 1984
; Finlay et al., 1986
; O'Leary and Stanfield, 1989
), the lack of contralateral connections of the ectopic neurons may result in greater con- nections with ipsilateral cortical areas, as reported here, and with thalamic nuclei. Further analyses may reveal a quantitative difference in both the cortical and thalamic connections in mice with ectopias, providing additional evidence of the altered ana- tomical organization of these animals.
Differences in connectivity like those reported here may contribute to the changes in neuron size seen in the thalamus of humans and rodents with early cortical malformation (Livingstone et al., 1991; Galaburda et al., 1994
; Sherman et al., 1995
; Jenner et al., 1996
; Herman et al., 1997
). It has been hypothesized that these thalamic changes result from the top- down effects of early cortical ectopias. Our tracer studies show that the ectopic neurons are connected with the thalamus, thus providing a pathway for thalamic changes. Changes in thalamic cell size and the alteration of contralateral cortical connections may play a role in the learning differences seen in mice and humans with molecular layer ectopias (Boehm et al., 1996a
,b
; Denenberg et al., 1991a
,b
; Schrott et al., 1992
, 1993
; Waters et al., 1997
).
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Notes |
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Address correspondence to Annette R. Jenner, Haskins Laboratories and Department of Pediatrics Yale School of Medicine, 270 Crown St, New Haven, CT 06511, USA. Email: jenner{at}haskins.yale.edu.
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Footnotes |
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References |
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