Gestational dexamethasone exposure impacts hippocampal excitatory synaptic transmission and learning and memory function with transgenerational effects

Mingcui Luo; Yiwen Yi; Songqiang Huang; Shiyun Dai; Lulu Xie; Kexin Liu; Shuai Zhang; Tao Jiang; Tingting Wang; Baozhen Yao; Hui Wang; Dan Xu

doi:10.1016/j.apsb.2023.05.013

Gestational dexamethasone exposure impacts hippocampal excitatory synaptic transmission and learning and memory function with transgenerational effects

Acta Pharm Sin B. 2023 Sep;13(9):3708-3727. doi: 10.1016/j.apsb.2023.05.013. Epub 2023 May 15.

Authors

Mingcui Luo^{1

2}, Yiwen Yi^{3

2}, Songqiang Huang^{3

2}, Shiyun Dai^{3

2}, Lulu Xie^{2

4}, Kexin Liu^{2

5}, Shuai Zhang^{1

2}, Tao Jiang^{3

2}, Tingting Wang^{1

2}, Baozhen Yao^{2

4}, Hui Wang^{3

2}, Dan Xu^{1

2}

Affiliations

¹ Department of Obstetrics, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
² Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
³ Department of Pharmacology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan 430071, China.
⁴ Department of Pediatrics, Renmin Hospital of Wuhan University, Wuhan 430071, China.
⁵ Department of Pharmacy, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.

Abstract

The formation of learning and memory is regulated by synaptic plasticity in hippocampal neurons. Here we explored how gestational exposure to dexamethasone, a synthetic glucocorticoid commonly used in clinical practice, has lasting effects on offspring's learning and memory. Adult offspring rats of prenatal dexamethasone exposure (PDE) displayed significant impairments in novelty recognition and spatial learning memory, with some phenotypes maintained transgenerationally. PDE impaired synaptic transmission of hippocampal excitatory neurons in offspring of F1 to F3 generations, and abnormalities of neurotransmitters and receptors would impair synaptic plasticity and lead to impaired learning and memory, but these changes failed to carry over to offspring of F5 and F7 generations. Mechanistically, altered hippocampal miR-133a-3p-SIRT1-CDK5-NR2B signaling axis in PDE multigeneration caused inhibition of excitatory synaptic transmission, which might be related to oocyte-specific high expression and transmission of miR-133a-3p. Together, PDE affects hippocampal excitatory synaptic transmission, with lasting consequences across generations, and CDK5 in offspring's peripheral blood might be used as an early-warning marker for fetal-originated learning and memory impairment.

Keywords: Dexamethasone; Early-warning marker; Hippocampus; Histon acetylation; Learning and memory impairment; MicroRNA; Synaptic transmission; Transgenerational inheritance.