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. 2009 Jul 1;29(26):8363-71.
doi: 10.1523/JNEUROSCI.3216-08.2009.

Mice with altered myelin proteolipid protein gene expression display cognitive deficits accompanied by abnormal neuron-glia interactions and decreased conduction velocities

Hisataka Tanaka  1 , Jianmei Ma, Kenji F Tanaka, Keizo Takao, Munekazu Komada, Koichi Tanda, Ayaka Suzuki, Tomoko Ishibashi, Hiroko Baba, Tadashi Isa, Ryuichi Shigemoto, Katsuhiko Ono, Tsuyoshi Miyakawa, Kazuhiro Ikenaka
Affiliations

Mice with altered myelin proteolipid protein gene expression display cognitive deficits accompanied by abnormal neuron-glia interactions and decreased conduction velocities

Hisataka Tanaka et al. J Neurosci. .

Abstract

Conduction velocity (CV) of myelinated axons has been shown to be regulated by oligodendrocytes even after myelination has been completed. However, how myelinating oligodendrocytes regulate CV, and what the significance of this regulation is for normal brain function remain unknown. To address these questions, we analyzed a transgenic mouse line harboring extra copies of the myelin proteolipid protein 1 (plp1) gene (plp1(tg/-) mice) at 2 months of age. At this stage, the plp1(tg/-) mice have an unaffected myelin structure with a normally appearing ion channel distribution, but the CV in all axonal tracts tested in the CNS is greatly reduced. We also found decreased axonal diameters and slightly abnormal paranodal structures, both of which can be a cause for the reduced CV. Interestingly the plp1(tg/-) mice showed altered anxiety-like behaviors, reduced prepulse inhibitions, spatial learning deficits and working memory deficit, all of which are schizophrenia-related behaviors. Our results implicate that abnormalities in the neuron-glia interactions at the paranodal junctions can result in reduced CV in the CNS, which then induces behavioral abnormalities related to schizophrenia.

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Figures

Figure 1.
Figure 1.
Impairment of cognitive task in the plp1 tg/− mice. A shows the results of probe test in Barnes spatial navigation task. Open bars indicate data of Wt mice, whereas black bars indicate those of plp1 tg/− mice. Wt mice spent significantly more time around the target than around any other holes when the probe test was conducted 1 d after the acquisition trials (A, # p < 0.01), whereas the plp1 tg/− mice did not. B and C show the percentage of correct choices in T-maze forced alternation task. The plp1 tg/− mice exhibited the lower correct responses during training session (B, *p < 0.05) and in 30 and 60 s delayed version (C, *p < 0.05), indicating that the working memory was impaired.
Figure 2.
Figure 2.
Axonal diameter changes in plp1 tg/− mice. A, B, Transverse sections of C3 spinal cord stained with toluidine blue to reveal the ventral funiculus in Wt mice (A) and plp1 tg/− mice (B). Comparing A and B, we found that axonal diameters in plp1 tg/− mice were relatively smaller than those of Wt mice, and that the myelin in plp1 tg/− mice was thinner than that in Wt mice. Scale bar: 10 μm. C, Histogram of myelinated axonal diameters showed that medium and large diameter axons (>3 μm) seemed to be replaced by small diameter fibers (<3 μm) in plp1 tg/− mice. The asterisk indicates the decreased number of axons with medium diameter, and the sharp indicates the increased number of axons with small diameter in plp1 tg/− mice.
Figure 3.
Figure 3.
A–D, Localization of Caspr (red) and Kv1.2 (green) at the paranodal junctions and juxtaparanodal area, respectively, in 2-month-old Wt (A) and plp1 tg/− mice (C). Caspr clusters (white) at the paranodal junctions in Wt (B) and plp1 tg/− mice (D). Note the dispersed distribution of Caspr clusters in plp1 tg/− mice (compare the red horizontal bars in B and D). The signals of Caspr and Kv1.2 showed considerable overlap in the paranodal area of plp1 tg/− mice (C). Scale bar: 10 μm. E, Histogram showing the distribution of the length of Caspr clusters in the VRST. The length of Caspr signals was elongated in plp1 tg/− mice.
Figure 4.
Figure 4.
A–D, Ultrastructure of paranode. A, D, Paranodal region of Wt (A) and plp1 tg/− (D) mice. B, C, Magnified images of the white boxes in A and C. Arrowheads in B show the septate-like junctions between the paranodal loops and the axolemma in a Wt mouse that has well formed and well preserved septate-like junctions (transverse bands). Arrowheads in D show the septate-like junctions in a plp1 tg/− mouse; however, a loss of septate-like junctions was observed in plp1 tg/− mice (C). E–G, Abnormal structures observed in plp1 tg/− mice: arrowheads in E show an everted paranodal myelin loop; arrowheads in F show a myelin outfolding; arrowheads in G show a myelin infolding. NR: node of Ranvier. Scale bars: (A, D), 300 nm; (E), 100 nm; (F, G), 1 μm.
Figure 5.
Figure 5.
Abnormal Caspr and Kv1.2 clustering in the corpus callosum. A, B, Immunostaining for Caspr (green) and Kv1.2 (red) shows that plp1 tg/− mice have many disrupted paranodes (B) compared with those of Wt mice (A). Note that intense Caspr signals were shortened and weak Caspr signals were scattered. Scale bar: 5 μm. C, Histogram showing the distribution of the length of intense Caspr signals in the corpus callosum (n = 300 each). Intense Caspr signals in plp1 tg/− mice were shorter than those in Wt mice.
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