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.
Jiahui Shi, Mei Chen, Yushu Zhang, Xiaotang Fan, Lian Wang, Huiling Liao
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引用次数: 0
Abstract
Rationale: 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.
Objective: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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