Association of impaired neuronal migration with cognitive deficits in extremely preterm infants
Ken-ichiro Kubo, … , Ken Inoue, Kazunori Nakajima
Ken-ichiro Kubo, … , Ken Inoue, Kazunori Nakajima
Published May 18, 2017
Citation Information: JCI Insight. 2017;2(10):e88609. https://doi.org/10.1172/jci.insight.88609.
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Research Article Development Neuroscience

Association of impaired neuronal migration with cognitive deficits in extremely preterm infants

Abstract

Many extremely preterm infants (born before 28 gestational weeks [GWs]) develop cognitive impairment in later life, although the underlying pathogenesis is not yet completely understood. Our examinations of the developing human neocortex confirmed that neuronal migration continues beyond 23 GWs, the gestational week at which extremely preterm infants have live births. We observed larger numbers of ectopic neurons in the white matter of the neocortex in human extremely preterm infants with brain injury and hypothesized that altered neuronal migration may be associated with cognitive impairment in later life. To confirm whether preterm brain injury affects neuronal migration, we produced brain damage in mouse embryos by occluding the maternal uterine arteries. The mice showed delayed neuronal migration, ectopic neurons in the white matter, altered neuronal alignment, and abnormal corticocortical axonal wiring. Similar to human extremely preterm infants with brain injury, the surviving mice exhibited cognitive deficits. Activation of the affected medial prefrontal cortices of the surviving mice improved working memory deficits, indicating that decreased neuronal activity caused the cognitive deficits. These findings suggest that altered neuronal migration altered by brain injury might contribute to the subsequent development of cognitive impairment in extremely preterm infants.

Authors

Ken-ichiro Kubo, Kimiko Deguchi, Taku Nagai, Yukiko Ito, Keitaro Yoshida, Toshihiro Endo, Seico Benner, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Minkyung Shin, Yuki Matsunaga, Kanehiro Hayashi, Masaki Kakeyama, Chiharu Tohyama, Kenji F. Tanaka, Kohichi Tanaka, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Yukio Hirata, Barbara Antalffy, Dawna D. Armstrong, Kiyofumi Yamada, Ken Inoue, Kazunori Nakajima

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Figure 8

The mouse model had cognitive impairments.

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The mouse model had cognitive impairments. (A) Schematic representation ...
(A) Schematic representation of the novel object recognition test. (B) Performance in the novel object recognition test (Control: n = 26, Occluded: n = 21). Left: exploratory index. Right: total exploration time. ***P < 0.001, repeated-measures ANOVA followed by Bonferroni post-hoc test. (C) Schematic representation of bilateral in utero electroporation into the mPFC at E15.0. An hM3Dq-mCherry–expressing vector (pCAG-hM3Dq-mCherry) was coelectroporated with pCAG-EGFP, followed by a sham operation (control) or maternal uterine artery occlusion (Occluded) at E16.5. (D) A representative image of the mPFC transfected with a GFP expression vector and hM3Dq-mCherry expression vector at E15.0 and fixed at P7 weeks. The section was stained with anti-RFP (magenta) antibody. Scale bar: 200 μm. (E) Scheme showing the time course of the injection of CNO or control saline and the behavioral test. (F) The graph indicates the spontaneous alternation behavior in the Y-maze test of the control/saline (n = 13), control/CNO (n = 12), occluded/saline (n = 12), and occluded/CNO (n = 13) mice. *P < 0.05, Tukey-Kramer test. (G) c-Fos expression in the prelimbic (PrL) region of the mPFC was analyzed by immunohistochemistry in the saline- and CNO-treated mice 2 hours after the Y-maze test. Images show representative examples of c-Fos expression in the PrL. Scale bar: 100 μm. (H) Quantitative analysis of the number of c-Fos–positive cells in the PrL from the control/saline, control/CNO, occluded/saline, and occluded/CNO mice (n = 6, respectively). *P < 0.05, Tukey-Kramer test. (B, F, and H) Each point represents an individual mouse. Box-and-whisker plots were used to graphically represent the median (line within box), upper and lower quartiles (bounds of box), and maximum and minimum values (top and bottom bars).