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

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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.

Abstract

Investigation of brains from extremely preterm human infants and a mouse model revealed that altered neuronal migration might contribute to subsequent cognitive impairment.

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Author and article information

Contributors

Ken-ichiro Kubo

Kimiko Deguchi:

ORCID: http://orcid.org/0000-0002-2697-6736

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:

ORCID: http://orcid.org/0000-0001-9063-9673

Chiharu Tohyama

Kohichi Tanaka:

ORCID: http://orcid.org/0000-0001-6929-4228

Sachio Takashima

Masahiro Nakayama

Masayuki Itoh

Yukio Hirata

Barbara Antalffy

Kiyofumi Yamada

Ken Inoue

Kazunori Nakajima:

ORCID: http://orcid.org/0000-0003-1864-9425

Journal

Journal ID (nlm-ta): JCI Insight

Journal ID (iso-abbrev): JCI Insight

Journal ID (publisher-id): JCI Insight

Title: JCI Insight

Publisher: American Society for Clinical Investigation

ISSN (Electronic): 2379-3708

Publication date Created: 18 May 2017

Publication date PMC-release: 18 May 2017

Volume: 2

Issue: 10

Electronic Location Identifier: e88609

Affiliations

[1 ]Department of Anatomy, Keio University School of Medicine, Tokyo, Japan.

[2 ]Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan.

[3 ]Department of Pathology, Baylor College of Medicine, Houston, Texas, USA.

[4 ]Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.

[5 ]Department of Molecular Neuroscience, Medical Research Institute/School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan.

[6 ]Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.

[7 ]Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

[8 ]Laboratory for Systems Neuroscience & Preventive Medicine, Waseda University Faculty of Human Sciences, Tokorozawa, Japan.

[9 ]Environmental Biology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

[10 ]Division of Child Neurology, Yanagawa Institute of Developmental Disabilities, Yanagawa, Japan.

[11 ]Department of Pathology, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan.

Author notes

Address correspondence to: Kazunori Nakajima or Ken-ichiro Kubo, Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Phone: 81.3.5363.3743; E-mail: kazunori@ 123456keio.jp (K. Namajima); kkubo@ 123456keio.jp (K. Kubo). Or to: Ken Inoue, Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan. Phone: 81.42.346.1713; E-mail: kinoue@ 123456ncnp.go.jp .

Authorship note: K. Kubo and K. Deguchi contributed equally to this work.