Early life stress impairs synaptic pruning in the developing hippocampus

Kiran K. Dayananda, Sahabuddin Ahmed, Daniel Wang, Baruh Polis, Rafiad Islam, Arie Kaffman

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Early life adversity impairs normal hippocampal function and connectivity in various mammalian species, including humans and rodents. According to the ‘cumulative model’ the number of early adversities can be summed up to determine the risk for developing psychopathology later in life. In contrast, the ‘dimensional model’ argues that ‘Deprivation’ and ‘Threat’ impact different developmental processes that should not be added in determining clinical outcomes. Here we examine these predictions in male and female mice exposed to a single adversity — limited bedding (LB) — versus mice exposed to multiple adversities — unpredictable postnatal stress (UPS) — focusing on microglia-mediated synaptic pruning in the developing hippocampus. Exposure to both LB and UPS reduced the ramification of microglia, impaired their ability to phagocytose synaptic material in vivo and ex vivo, and decreased expression of TREM2. Abnormal phagocytic activity was associated with increased spine density in CA1 pyramidal neurons that was seen in 17-day-old groups and persisted in peri-pubescent 29-day-old LB and UPS mice. Exposure to LB caused more severe impairment in microglial ramification and synaptic engulfment compared to UPS, outcomes that were accompanied by a UPS-specific increase in the expression of several genes implicated in synaptic pruning. We propose that despite being a single stressor, LB represents a more severe form of early deprivation, and that appropriate levels of hippocampal stimulation during the second and third weeks of life are necessary to support normal microglial ramification and synaptic pruning. Further, impaired synaptic pruning during this critical period of hippocampal development contributes to the abnormal hippocampal function and connectivity seen in UPS and LB later in life.

Original languageEnglish
Pages (from-to)16-31
Number of pages16
JournalBrain, Behavior, and Immunity
Volume107
DOIs
StatePublished - Jan 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 The Authors

Funding

This work was supported by: NIMH R01MH119164 , NIMH R01MH118332 , and the Clinical Neuroscience Division of the VA National Center for PTSD.

FundersFunder number
National Institute of Mental HealthR01MH119164, R01MH118332
National Center for PTSD, U.S. Department of Veterans Affairs

    Keywords

    • Early life stress
    • Hippocampus
    • Limited bedding and nesting
    • Mice
    • Microglia
    • Synaptic pruning

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