Instituto Cajal, CSIC, E-28002 Madrid, Spain
J. DeFelipe, Instituto Cajal, CSIC, Avda. Doctor Arce 37, E-28002 Madrid, Spain. Email: defelipe{at}cajal.csic.es.
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Abstract |
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Introduction |
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PSA-NCAM is highly expressed during development (late embryonic and early postnatal periods), when it is involved in neuronal migration, neurite extension, pathfinding and synapto-genesis (Sunshine et al., 1987; Doherty et al., 1990
; Landmesser et al., 1990
; Tang et al., 1992
; Seki and Arai, 1993
; Szele et al., 1994
; Fields and Itoh, 1996
). NCAM polysialylation exhibits an age-related decline and PSA-NCAM is progressively replaced, as development proceeds, by non-sialylated adult forms of NCAM that have increased adhesion properties and stabilize newly formed contacts (Edelman and Chuong, 1982
; Hoffman et al., 1982
; Rothbard et al., 1982
; Finne et al., 1983
; Sadoul et al., 1983
; Rutishauser et al., 1988
; Doherty et al., 1990
; Chung et al., 1991
; Troy, 1992
; Fox et al., 1995
; Fields and Itoh, 1996
).
In the adult brain, PSA-NCAM expression is considerably reduced, although it has been shown to be highly expressed in certain areas (e.g. the olfactory bulb and hippocampus), where it is thought to negatively regulate cellcell interactions, facilitating the occurrence of structural changes (Miragall et al., 1988; Aaron and Chesselet, 1989
; Chung et al., 1991
; Theodosis et al., 1991
; Bonfanti et al., 1992
; Seki and Arai, 1993
; Miller et al., 1993
; Muller et al., 1996
; Cremer et al., 2000
). In the adult human entorhinal cortex, previous workers (Mikkonen et al., 1998
, 1999
) have described the presence of 2050 µm long PSA-NCAM-immunoreactive, vertically oriented processes in layers II and III that were described as fiber bundles. While examining human cortical tissue immunocytochemically stained for PSA-NCAM, we also observed the presence of such processes, which according to our criteria, were identified as chandelier cell axon terminals (chandelier terminals).
Chandelier cells are considered to be the most powerful GABAergic interneuron of the cerebral cortex, forming synapses exclusively with the axon initial segments of pyramidal cells (Szentágothai and Arbib, 1974; Fairén and Valverde, 1980
; Peters et al., 1982
; Somogyi et al., 1982
, 1983a
, Somogyi et al., b
, 1985
; Freund et al., 1983
; DeFelipe et al., 1985
). Chandelier terminals can be visualized using immunocytochemistry for the calcium-binding protein parvalbumin (PV) and the GABA transporter GAT-1 (DeFelipe, 1999
). In addition, immunocytochemical staining for 5-HT1A can be used to label the axon initial segments of pyramidal cells (DeFelipe et al., 2001
). Therefore, in the present study we have used double-labeling immunocytochemical techniques to verify the presence of PSA-NCAM immunolabeling in chandelier terminals in the adult human entorhinal cortex and temporal neocortex.
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Materials and Methods |
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After fixation, the blocks were cut serially at 50 or 100 µm with a Vibratome and the sections were pretreated with a solution of ethanol and hydrogen peroxidase in PB to remove endogenous peroxidase activity. Sections were then processed by immunoperoxidase or double-labeling immunoflurorescence techniques for light/fluorescent microscopy. All antisera and antibodies used were diluted in PB containing 3% normal serum of the species in which the secondary antibody was raised, 2% bovine serum albumin and 0.25% Triton X-100 (stock solution).
Single Immunoperoxidase Staining
Free-floating sections were preincubated for 1 h in stock solution and then incubated for 3648 h at 4°C in stock solution containing mouse anti-PSA-NCAM (1:6000, IgM, 5A5; Developmental Studies Hybridoma Bank, IA), rabbit anti-PV (1:4000, Swant; Bellinzona, Switzerland), rabbit anti-GAT-1 (1:2000, Chemicon; Temecula, CA) or rabbit anti-5-HT1A (1:1500) (Azmitia et al., 1992). The monoclonal antibodies against PSA-NCAM that were used specifically recognize the polysialyglycan chain of NCAM. These antibodies were purified from hybridoma cells obtained by the fusion of NS1 cells and mice spleen cells immunized with membrane preparations from E14E15 rat spinal cord (Dodd et al., 1988
).
The sections were then processed by the avidinbiotinperoxidase method, using secondary goat anti-mouse IgM or goat anti-rabbit biotinylated antibodies (1:200; Vector Laboratories, Burlingame, CA) and the Vectastain ABC immunoperoxidase kit (Vector). Sections were reacted histochemically with 0.05% 3,3'-diaminobenzidine tetrahydrochloride (DAB; Sigma, St Louis, MO) and 0.01% hydrogen peroxide. Finally, sections were mounted onto glass slides, dehydrated, cleared with xylene and coverslipped. Adjacent sections were stained with thionin to reveal laminar boundaries and regional borders of the temporal cortex.
Double Immunofluorescence Staining
Sections were double-stained for PSA-NCAM and PV, PSA-NCAM and GAT-1 or PSA-NCAM and 5-HT1A, using the same primary antibodies, dilutions and incubation times as indicated above. Sections were first incubated in a solution containing the primary antisera (anti-PV, anti-GAT-1 or anti-5-HT1A) and then incubated for 2 h at room temperature in goat anti-rabbit antibodies coupled to Alexa 594 (1:1000; Molecular Probes, Eugene, OR). After rinsing in PB, sections were incubated in a solution containing anti-PSA-NCAM antibodies and then incubated in biotinylated horse anti-mouse IgM antibodies (1:200; Vector). Thereafter, sections were incubated for 2 h at room temperature in streptoavidin coupled to Alexa fluor 488 (1:1000; Molecular Probes), washed and mounted in 50% glycerol in PB. Sections were examined in a Leica TCS 4D confocal laser scanning system attached to a Leitz DMRIB microscope and equipped with an argon/krypton mixed gas laser with excitation peaks at 489 nm (for Alexa 488-labeled profiles) and 649 nm (for Alexa 594-labeled profiles). The fluorescence of profiles labeled with each chromogen was recorded through separate channels. Z-sectioning was performed at 1.52 µm intervals, and optical stacks of four to seven images were used for figures.
For all immunocytochemical procedures, controls consisted of processing selected sections either after replacing the primary antibody with preimmune goat or horse serum, after omission of the secondary antibody, or after replacement of the secondary antibody with an inappropriate secondary antibody. No significant staining was detected under these control conditions.
To quantify the percentage of colocalization of PSA-NCAM and PV or PSA-NCAM and GAT-1 in chandelier terminals, counts of single- and double-labeled profiles were made in sections from the entorhinal cortex and neocortex of two humans. For each double-labeling combination and individual case, a total of 10 randomly selected microscopic fields (160 000 µm2 each) from layers II and III were used to estimate the percentage of colocalization.
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Results |
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In both the entorhinal cortex and neocortex, PSA-NCAM immunocytochemistry revealed the presence of numerous immunoreactive (-ir) elements that include cell bodies, terminal- like puncta in the neuropil and surrounding unstained cell bodies (basket formations), dendritic processes, fibers and chandelier terminals (short, vertically-oriented rows of buttons; Figs 13). The morphology of chandelier terminals was clearly identified (DeFelipe et al., 1989
) and distinguished from other immunoreactive elements. Furthermore, chandelier terminals were more intensely immunostained than other processes (Fig. 3
). Since the general pattern of PSA-NCAM immunostaining has been described in the human cortex (Mikkonen et al., 1998
, 1999
), we will refer only to chandelier terminal-labeling unless otherwise specified.
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PV and GAT-1 immunocytochemistry revealed the presence of chandelier terminals with density and distribution patterns similar to those of the PSA-NCAM-ir processes in layers II and III of the entorhinal cortex and temporal neocortex (Figs 13). Moreover, PV (Fig. 2
) and GAT-1 immunostaining showed the presence of numerous chandelier terminals in layer VI of the entorhinal cortex and in layers IVVI of the temporal neocortex.
In double-labeling experiments, high rates of colocalization of PSA-NCAM and PV, as well as PSA-NCAM and GAT-1 in chandelier terminals, were found in layers II and III of both cortical areas (Fig. 3, Table 1
). Nearly all chandelier terminals labeled for PV or GAT-1 in the entorhinal cortex (95 and 94.5%, respectively) and in the neocortex (93 and 92%, respectively) coexpressed PSA-NCAM (Table 1
). In addition, as shown in Table 1
, most PSA-NCAM-ir chandelier terminals colocalized PV (Fig. 3A
C) and GAT-1 (Fig. 3D
F) in both cortical areas. Thus, PSA-NCAM immunocytochemistry labels a subpopulation of chandelier terminals, most of which coexpress PV and GAT-1.
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Discussion |
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The expression of PSA-NCAM was not only confined to chandelier terminals. Other immunoreactive elements, such as terminal-like puncta, dendrites and fibers, were frequently found, although less intensely stained. These latter PSA-NCAM-ir elements have previously been described in the human cortex (Mikkonen et al., 1998, 1999
). Thus, in the following sections we will only refer to chandelier terminals.
PSA-NCAM-ir Chandelier Terminals: Possible Functional Roles
The expression of PSA and NCAM in different brain regions has a fast turnover and is regulated by neuronal and synaptic activity (Landmesser et al., 1990; Theodosis et al., 1991
; Doyle et al., 1992
; Kiss et al., 1994
; Muller et al., 1996
; Kiss and Rougon, 1997
; Nothias et al., 1997
; Ronn et al., 2000
). Interestingly, earlier workers (Mikkonen et al., 1998
) found an increase in PSA-NCAM neuropil staining and a decrease in the number of fiber bundles in layer II of the entorhinal cortex of patients with temporal lobe epilepsy. According to the present data, this decrease might be related to the loss of chandelier terminals in temporal cortical regions found in epileptic patients (DeFelipe, 1999
). We speculate that changes in chandelier cell activity, by up- or down-regulating the expression of PSA-NCAM, might promote structural and/or functional reorganization of the inhibitory synaptic input to pyramidal cells. Furthermore, a decrease in the number of supragranular GAT1-positive chandelier cell axon terminals has been reported in areas 9 and 46 of patients suffering schizophrenia (Lewis et al., 1999
; Lewis, 2000
). Thus, it will be interesting to know whether PSA-NCAM-ir chandelier terminals are affected or not in these patients.
The presence of PSA-NCAM in chandelier terminals suggests that this glycoprotein makes heterophilic contacts with a different adhesion molecule present in the pyramidal cell axon membrane. For example, adhesion proteins of the L1-CAM family, such as neurofascin and NrCAM, which play important roles as binding partners for NCAM, are concentrated at the axon initial segment and nodes of Ranvier in different neuronal types, where they are involved in the restriction of voltage-gated sodium channels to these locations (Davis et al., 1996; Hortsch, 1996
; Brummendorf et al., 1998
; Bennett and Lambert, 1999
). It is, therefore, possible that PSA-NCAM from chandelier terminals interacts with L1-CAM adhesion proteins of the pyramidal cell axon initial segment. Further electron microscopy double-labeling immunogold studies are necessary to examine this possibility.
Based on what is known about cell adhesion molecules, PSA-NCAM in chandelier terminals might have the following functions. (i) The maintenance of a weak adhesion to the pyramidal cell axons they surround. This would confer a permissive environment for the structural remodeling of the contacts between axons of both cell types. (ii) PSA-NCAM might influence the physiological parameters of the axo-axonic synapses, since, in other cell types, PSA-NCAM affects second messenger systems and triggers intracellular signal transduction events (Schuch et al., 1989; Doherty et al., 1991
; Doherty and Walsh, 1992
, 1994
; Muller et al., 2000
). (iii) PSA-NCAM might be involved in synaptic plasticity, as expression of NCAM, PSA-NCAM and adhesion proteins of the L1 family are essential for the induction of activity-induced forms of physiological plasticity, such as LTP and LTD, in both excitatory and inhibitory synapses (Becker et al., 1996
; Luthi et al., 1996
; Muller et al., 1996; Cotman et al., 1998
; Cremer et al., 2000
). In addition, removing PSA from NCAM with endoneuraminidase-N impairs LTP in CA1 cells and impairs the acquisition and retention of spatial memory in rats (Becker et al., 1996
; Muller et al., 1996
; Ronn et al., 2000
).
Therefore, chandelier cells may be important not only for the inhibitory control of pyramidal cell activity (DeFelipe, 1999), but also in activity-dependent plastic changes of pyramidal cells.
Functional Implications of the Laminar Distribution of PSA-NCAM-ir Chandelier Terminals
Chandelier terminals are present throughout layers IIVI of the human entorhinal cortex and neocortex (Fonseca et al., 1993; Schmidt et al., 1993
; del Rio and DeFelipe, 1994
), whereas those immunolabeled for PSA-NCAM were found mostly in layers II and III. The entorhinal cortex is part of the mesial temporal structures involved in the consolidation of declarative memory and plays a pivotal role in gating the flow of cortical information to the hippocampus (Amaral, 1993
; Witter, 1993
; Squire and Zola, 1996
). Pyramidal cells located in layers II and III of the entorhinal cortex give rise to the main source of cortical input to the hippocampus through the perforant pathway (Amaral, 1993
; Witter, 1993
). The high expression of PSA-NCAM found in chandelier terminals in layers IIIII of the entorhinal cortex suggests that the modulation of cortical input to the hippo-campus by chandelier cells is highly susceptible to plastic changes, a feature that could be particularly relevant to the process of memory consolidation. Similarly, pyramidal cells located in different layers of the neocortex project to different targets (Jones, 1984
; White, 1989
; Rockland, 1997
). The projections arising from supragranular pyramidal cells participate in the control of temporal cortico-cortical networks involved in high-order associative processes. Thus, the selective expression of PSA-NCAM found in supragranular layers of the cortex suggests that the modulation of specific projection pathways, by PSA-NCAM-expressing chandelier cells, may be more susceptible to plastic changes than others. Whether alterations in behaviour associated with certain mental disorders such as schizophrenia are related to plastic alterations of specific projections as the result of changes in PSA-NCAM expression in chandelier cell axons is a possibility that should be explored in future studies.
Finally, the present results, together with previous studies showing laminar differences in the expression of 5-HT1A sero-tonin receptors (DeFelipe et al., 2001) and in the subunit composition of GABAA receptors (Fritschy et al., 1998
) in the proximal portion of pyramidal cell axons, further support the existence of remarkable differences in the relationship between chandelier cells and pyramidal cells in supragranular versus infragranular layers.
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Acknowledgments |
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