Prenatal Stress Leads to the Altered Maturation of Corticostriatal Synaptic Plasticity and Related Behavioral Impairment
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ORIGINAL ARTICLE
Prenatal Stress Leads to the Altered Maturation of Corticostriatal Synaptic Plasticity and Related Behavioral Impairments Through Epigenetic Modifications of Dopamine D2 Receptor in Mice Yingchun Li 1 & Jing Rong 1 & Haiquan Zhong 1 & Min Liang 1 & Chunting Zhu 1 & Fei Chang 1 & Rong Zhou 1 Received: 12 May 2020 / Accepted: 8 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Prenatal stress (PRS) had a long-term adverse effect on motor behaviors. Corticostriatal synaptic plasticity, a cellular basis for motor controlling, has been proven to participate in the pathogenesis of many behavior disorders. Based on the reports about the involvement of epigenetic DNA alterations in PRS-induced long-term effects, this research investigated the influence of PRS on the development and maturation of corticostriatal synaptic plasticity and related behaviors and explored the underlying epigenetic mechanism. Subjects were male offspring of dams that were exposed to stress three times per day from the 10th day of pregnancy until delivery. The development and maturation of plasticity at corticostriatal synapses, dopamine signaling, behavioral habituation, and DNA methylation were examined and analyzed. Control mice expressed long-term potentiation (LTP) at corticostriatal synapses during postnatal days (PD) 12–14 and produced long-term depression (LTD) during PD 20–60. However, PRS mice exhibited sustained LTP during PD 12–60. The treatment with dopamine 2 receptor (D2R) agonist quinpirole recovered striatal LTD and improved the impaired behavioral habituation in PD 45 adult PRS mice. Additionally, adult PRS mice showed reduced D2R, excess DNA methyltransferase 1 (DNMT1), increased binding of DNMT1 to D2R promoter, and hypermethylation at D2R promoter in the striatum. The DNMT1 inhibitor 5-aza-deoxycytidine restored striatal synaptic plasticity and improved behavioral habituation in adult PRS mice via D2R-mediated dopamine signaling. DNMT1-associated D2R hypermethylation is responsible for altering the maturation of plasticity at corticostriatal synapses and impairing the behavioral habituation in PRS mice. Keywords PRS . Striatum . Synaptic plasticity . Behavioral habituation . DNA methylation . Dopamine
Introduction Stress in early-life, especially in prenatal life, has programming effects on the central nervous system in postnatal life. Several studies have reported that prenatal stress (PRS) is associated with cognitive deficits, emotional abnormality, and motor dysfunction [1–3]. To date, the mechanisms by which PRS impairs cognition and emotion have been widely concerning. However, few studies focus on the mechanisms underlying the adverse effect of PRS on motor behaviors. The neocortex provides major glutamatergic inputs to striatal medium spiny projection neurons. Plasticity at corticostriatal
* Rong Zhou [email protected] 1
Department of Physiology, Nanjing Medical University, Longmian Avenue 101, Jiangning District, Nanjing City 211166, Jiangsu Province, Ch
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