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.

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 OBJECTIVE: This study aimed to investigate the therapeutic effects and potential molecular mechanisms of RosA in alleviating behavioral dysfunction in Shank3B 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 CONCLUSION: RosA alleviates cognitive deficits and repetitive behaviors in Shank3B