Targeting synaptic plasticity and acetylcholine dysregulation in the medial prefrontal cortex: Rosmarinic acid attenuates Autism-like phenotypes in Shank3B^-/- mice via the CREB/BDNF pathway.

Authors

Jiahui Shi, Mei Chen, Yushu Zhang, Xiaotang Fan, Lian Wang, Huiling Liao

Published in

Psychopharmacology. Sep 27, 2025. Epub Sep 27, 2025.

Abstract

Autism spectrum disorder (ASD) is characterized by cognitive deficits, repetitive behaviors, and social impairments. The SH3 and multiple ankyrin repeat domains protein 3B-deficient (Shank3B^-/-) mouse model displays ASD-related phenotypes. While rosmarinic acid (RosA) is known for its neuroprotective properties, its role in ASD remains unclear.
This study aimed to investigate the therapeutic effects and potential molecular mechanisms of RosA in alleviating behavioral dysfunction in Shank3B^-/- mice. We assessed core ASD-like behavioral indices, performed bioinformatics predictions, and validated the results through molecular biology experiments.
Social deficits were evaluated using the three-chamber social test and the male-male social interaction test. Repetitive behaviors were assessed through the self-grooming and marble-burying tests. Cognitive and memory functions were measured using novel object recognition, the Y-maze, and nesting behavior tests. The open field test was employed to evaluate motor functions and exploratory activities. High-throughput RNA sequencing (RNA-seq) was used to identify key genes in the medial prefrontal cortex (mPFC) of the different groups of mice. Neurotransmitter levels of acetylcholine (ACh) and γ-aminobutyric acid (GABA) were analyzed via ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and high-performance liquid chromatography (HPLC), respectively. Additionally, synaptic function and plasticity in the mPFC were assessed by measuring Postsynaptic Density Protein 95 (PSD95) expression and the activation of the p-CREB/BDNF signaling pathway.
RosA significantly improved repetitive behaviors, as well as cognitive and memory abilities, in Shank3B^-/- mice. It also enhanced motor functions and exploratory activities. However, RosA did not show significant therapeutic effects on social deficits. RNA-seq analysis revealed that RosA notably regulated synaptic proteins. Molecular biology experiments indicated that RosA upregulated PSD95 expression and activated the p-CREB/BDNF signaling pathway in the mPFC, enhancing synaptic plasticity. RosA also increased ACh levels without affecting GABA, indicating a cholinergic mechanism. No significant effects were observed in wild-type (WT) mice, suggesting specificity to ASD-related deficits.
RosA alleviates cognitive deficits and repetitive behaviors in Shank3B^-/- mice through CREB/BDNF-mediated synaptic and cholinergic regulation in the mPFC. However, its lack of effect on social deficits suggests distinct mechanisms underlying ASD symptoms. These findings highlight the potential of RosA as a targeted ASD therapy.

PMID:
41014339
Bibliographic data and abstract were imported from PubMed on 27 Sep 2025.

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