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 6

The mouse model showed an altered neuronal alignment.

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The mouse model showed an altered neuronal alignment. (A) After transfec...
(A) After transfection of GFP plasmid at E15.0, a sham operation (Control) or maternal uterine artery occlusion (Occluded) was performed at E16.5 and followed by BrdU injection at E17.0. Brains were analyzed at P10. Sections were immunostained with anti-BrdU antibody (magenta). Right panels show the bin analysis of the distribution of GFP-positive cells and BrdU-positive cells (mean ± SEM; n = 4, respectively). *P < 0.05, **P < 0.01, ***P < 0.001, repeated-measures ANOVA followed by Bonferroni post-hoc test. Scale bar: 100 μm. (B) High-magnification images of the superficial areas of the neocortices in A. Scale bar: 100 μm. (C) A sham operation or maternal uterine artery occlusion was performed at E16.5 and followed by BrdU injection at E17.0. Brains were analyzed at P10. Sections were immunostained with anti-NeuN antibody (green) and anti-BrdU antibody (magenta). Scale bar: 100 μm. (D) High-magnification images of the white matter (WM) in C. Scale bar: 50 μm. (E) The number of BrdU-positive cells (left) and NeuN-positive cells (right) in the WM (n = 8, respectively) are shown. ***P < 0.001, Welch’s t test. 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).