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. 2013 Mar:241:5-12.
doi: 10.1016/j.expneurol.2012.11.028. Epub 2012 Dec 7.

Depletion of polysialic acid from neural cell adhesion molecule (PSA-NCAM) increases CA3 dendritic arborization and increases vulnerability to excitotoxicity

Trudy McCall  1 , Zachary M Weil, Juan Nacher, Erik B Bloss, Abderrahman El Maarouf, Urs Rutishauser, Bruce S McEwen
Affiliations

Depletion of polysialic acid from neural cell adhesion molecule (PSA-NCAM) increases CA3 dendritic arborization and increases vulnerability to excitotoxicity

Trudy McCall et al. Exp Neurol. 2013 Mar.

Abstract

Chronic immobilization stress (CIS) shortens apical dendritic trees of CA3 pyramidal neurons in the hippocampus of the male rat, and dendritic length may be a determinant of vulnerability to stress. Expression of the polysialylated form of neural cell adhesion molecule (PSA-NCAM) in the hippocampal formation is increased by stress, while PSA removal by Endo-neuraminidase-N (endo-N) is known to cause the mossy fibers to defasciculate and synapse ectopically in their CA3 target area. We show here that enzymatic removal of PSA produced a remarkable expansion of dendritic arbors of CA3 pyramidal neurons, with a lesser effect in CA1. This expansion eclipsed the CIS-induced shortening of CA3 dendrites, with the expanded dendrites of both no-stress-endo-N and CIS-endo-N rats being longer than those in no-stress-control rats and much longer than those in CIS-control rats. As predicted by the hypothesis that endo-N-induced dendritic expansion might increase vulnerability to excitotoxic challenge, systemic injection with kainic acid, showed markedly increased neuronal degeneration, as assessed by fluorojade B histochemistry, in rats that had been treated with endo-N compared to vehicle-treated rats throughout the entire hippocampal formation. PSA removal also exacerbated the CIS-induced reduction in body weight and abolished effects of CIS on NPY and NR2B mRNA levels. These findings support the hypothesis that CA3 arbor plasticity plays a protective role during prolonged stress and clarify the role of PSA-NCAM in stress-induced dendritic plasticity.

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Figures

Figure 1
Figure 1
PSA-NCAM immunohistochemistry in the hippocampal CA3 region. A. Panoramic view showing the presence of intense PSA-NCAM immunostaining in the stratum lucidum. An interneuronal soma (arrow) and several processes, probably belonging to interneurons, can be observed in the stratum radiatum. Some scarce immunoreactive processes can also be found in the stratum oriens. B. Detailed view of the CA3 region. Thick processes belonging to mossy fibers can be observed in the stratum lucidum. Thinner processes also can be seen traversing the stratum pyramidale and oriens. S.L.: stratum lucidum; S.O.: stratum oriens; S.P: stratum pyramidale; S.R.: stratum radiatum. Figure A is a 2D projection of 10 confocal planes and B is a single confocal plane. Scale bar: 100 μm for A and 25 μm for B.
Figure 2
Figure 2
PSA removal exaggerated CIS effects on body mass growth. Rats at the age used in this study are typically still gaining body mass, and endoN treatment alone did not affect this growth. However, chronic stress slowed this weight gain, and PSA removal by endoN exacerbated this CIS effect. * Indicates significantly different from no stress groups in the same injection type; #Indicates significantly different than stress-endoN group. Body mass growth was completely suppressed by CIS in the absence of PSA. Data are presented as means (± SEM), N=8–9/group.
Figure 3
Figure 3
Expression of NMDA receptor subunit genes. CIS or endoN did not produce any change in NR2A mRNA levels in the dentate gyrus that could be detectable by in situ hybridization. However, NR2B gene expression was reduced by CIS, an effect that was blocked by endoN treatment. * Indicates significant differences at P<0.05. Data are presented as means (±SEM) N=9–10/group.
Figure 4
Figure 4
PSA removal antagonized the specific effect of CIS on dendritic branches. Top: Representative camera lucida traces from Vehicle and endoN -treated rats that were exposed to ten days of CIS. The dendritic arbors were larger in endoN -treated animals. Bottom: (A) CIS shortened the total length of CA3 dendritic arbor while PSA removal produced an increase in these measures. With combination of CIS and ENDO-N, the total arbor length was shorter than with endoN alone but still larger that control values. (B) Interestingly, the effects on numbers of branching points followed a similar pattern. (C) Sholl analysis revealed that PSA removal alone produced an elongation of branches located at all distances from the soma (from 0 to 550 μm approximately), while CIS alone specifically shortened branches located near the soma (approximately between 100 and 250 μm). Interestingly, PSA removal completely antagonized this CIS-induced dendrite atrophy. Data are presented as means (±SEM) N=9–10/group.
Figure 5
Figure 5
ENDO-N treatment exacerbates kainate-induced hippocampal degeneration independent of stress conditions. EndoN increased cell death independent of stress conditions (p<0.05). Sections were stained with Fluorojade B histochemistry and total degenerating hippocampal cells were counted. Data are presented as means (±SEM) N=4–5/group.
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