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Early postnatal stress suppresses the developmental trajectory of hippocampal pyramidal neurons: the role of CRHR1

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Abstract

Adverse experiences early in life hamper the development and maturation of the hippocampus, but how early-life stress perturbs the developmental trajectory of the hippocampus across various life stages and the underlying molecular mechanisms remain to be investigated. In this study, we stressed male mice from postnatal day 2 (P2) to P9, and examined the potential role of CRHR1 in postnatal stress-induced structural remodeling of hippocampal CA3 pyramidal neurons directly after stress (P9), in mid-adolescence (P35) and in adulthood (P90). We found that early-life stress exposure significantly reduced apical dendritic arborization and spine density in CA3 neurons on P9 and P90. Moreover, postnatally stressed neurons underwent increased pruning of spines, especially thin spines, between P35 and P90. These stress-induced immediate and long-term structural abnormalities could be abolished by daily systemic administration of the CRHR1 antagonist antalarmin (20 µg/g of body weight) during stress exposure. However, such treatment strategy failed to attenuate the deleterious stress effects in mid-adolescence on P35. We then extended antalarmin treatment until the end of the second postnatal week, and found that prolonged blockade of CRHR1 could prevent the mid-term impact of early postnatal stress on structural remodeling of CA3 neurons. Our study characterized the influences of early-life stress on the developmental trajectory of hippocampal pyramidal neurons, and highlighted the critical role of CRHR1 in modulating these negative outcomes evoked by early-life stress.

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Acknowledgments

We thank Dr. Mathias V. Schmidt (Max Planck Institute of Psychiatry) for discussion and critical reading of the manuscript, and thank Prof. Yi Rao and Dr. Xian Zhang (Peking University) for the use of the Neurolucida system. This work was supported by the National Natural Science Foundation of China (Grant Numbers 81171284, 81301152 and 81471369) and the Research Fund for the Doctoral Program of Higher Education of China (Number 20120001110046). All authors reported no biomedical financial interests or potential conflicts of interest.

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Authors and Affiliations

  1. Peking University Sixth Hospital (Institute of Mental Health), Beijing, 100191, China

    Rui Liu, Xiao-Dun Yang, Xue-Mei Liao, Xiao-Meng Xie, Yun-Ai Su, Ji-Tao Li & Tian-Mei Si

  2. National Clinical Research Center for Mental Disorders & Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, 100191, China

    Rui Liu, Xiao-Dun Yang, Xue-Mei Liao, Xiao-Meng Xie, Yun-Ai Su, Ji-Tao Li & Tian-Mei Si

  3. Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Xiao-Dong Wang

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  1. Rui Liu
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Liu, R., Yang, XD., Liao, XM. et al. Early postnatal stress suppresses the developmental trajectory of hippocampal pyramidal neurons: the role of CRHR1. Brain Struct Funct 221, 4525–4536 (2016). https://doi.org/10.1007/s00429-016-1182-4

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