Prenatal exposure to valproic acid reduces synaptic δ-catenin levels and disrupts ultrasonic vocalization in neonates.

Autor: Roh SH; Department of Biomedical Sciences, USA., Mendez-Vazquez H; Department of Biomedical Sciences, USA., Sathler MF; Department of Biomedical Sciences, USA., Doolittle MJ; Molecular, Cellular and Integrative Neurosciences Program, USA., Zaytseva A; Molecular, Cellular and Integrative Neurosciences Program, USA., Brown H; Department of Biology, USA., Sainsbury M; Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, 80523, USA., Kim S; Department of Biomedical Sciences, USA; Molecular, Cellular and Integrative Neurosciences Program, USA. Electronic address: seonil.kim@colostate.edu.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2024 Aug 01; Vol. 253, pp. 109963. Date of Electronic Publication: 2024 Apr 23.
DOI: 10.1016/j.neuropharm.2024.109963
Abstrakt: Valproic acid (VPA) is an effective and commonly prescribed drug for epilepsy and bipolar disorder. However, children born from mothers treated with VPA during pregnancy exhibit an increased incidence of autism spectrum disorder (ASD). Although VPA may impair brain development at the cellular level, the mechanism of VPA-induced ASD has not been completely addressed. A previous study has found that VPA treatment strongly reduces δ-catenin mRNA levels in cultured human neurons. δ-catenin is important for the control of glutamatergic synapses and is strongly associated with ASD. VPA inhibits dendritic morphogenesis in developing neurons, an effect that is also found in neurons lacking δ-catenin expression. We thus hypothesize that prenatal exposure to VPA significantly reduces δ-catenin levels in the brain, which impairs glutamatergic synapses to cause ASD. Here, we found that prenatal exposure to VPA markedly reduced δ-catenin levels in the brain of mouse pups. VPA treatment also impaired dendritic branching in developing mouse cortical neurons, which was partially reversed by elevating δ-catenin expression. Prenatal VPA exposure significantly reduced synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor levels and postsynaptic density 95 (PSD95) in the brain of mouse pups, indicating dysfunctions in glutamatergic synaptic transmission. VPA exposure also significantly altered ultrasonic vocalization (USV) in newly born pups when they were isolated from their nest. Moreover, VPA-exposed pups show impaired hypothalamic response to isolation, which is required to produce animals' USVs following isolation from the nest. Therefore, these results suggest that VPA-induced ASD pathology can be mediated by the loss of δ-catenin functions.
Competing Interests: Declaration of competing interest All authors declare no conflicts of interest.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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