Enhancing social behavior in an autism spectrum disorder mouse model: investigating the underlying mechanisms of Lactiplantibacillus plantarum intervention

ABSTRACT

Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting over 1% of the global population. Individuals with ASD often exhibit complex behavioral conditions, including significant social difficulties and repetitive behaviors. Moreover, ASD often co-occurs with several other conditions, including intellectual disabilities and anxiety disorders. The etiology of ASD remains largely unknown owing to its complex genetic variations and associated environmental risks. Ultimately, this poses a fundamental challenge for the development of effective ASD treatment strategies. Previously, we demonstrated that daily supplementation with the probiotic Lactiplantibacillus plantarum PS128 (PS128) alleviates ASD symptoms in children. However, the mechanism underlying this improvement in ASD-associated behaviors remains unclear. Here, we used a well-established ASD mouse model, induced by prenatal exposure to valproic acid (VPA), to study the physiological roles of PS128 in vivo. Overall, we showed that PS128 selectively ameliorates behavioral abnormalities in social and spatial memory in VPA-induced ASD mice. Morphological examination of dendritic architecture further revealed that PS128 facilitated the restoration of dendritic arborization and spine density in the hippocampus and prefrontal cortex of ASD mice. Notably, PS128 was crucial for restoring oxytocin levels in the paraventricular nucleus and oxytocin receptor signaling in the hippocampus. Moreover, PS128 alters the gut microbiota composition and increases the abundance of Bifidobacterium spp. and PS128-induced changes in Bifidobacterium abundance positively correlated with PS128-induced behavioral improvements. Together, our results show that PS128 treatment can effectively ameliorate ASD-associated behaviors and reinstate oxytocin levels in VPA-induced mice, thereby providing a promising strategy for the future development of ASD therapeutics.

KEYWORDS:

• Gut microbiota
• valproic acid
• ASD mouse model
• paraventricular nucleus
• hippocampus
• dendritic arborization
• neuronal connectivity

Acknowledgments

We thank the Laboratory Animal Facility and Imaging Core facility of ICOB, Academia Sinica for the animal care and imaging assistance. We also thank Taiwan Genomic Industry Alliance Inc. for sequencing and bioinformatics services, Leeuwenhoek Laboratories for metabolite analysis, the Transgenic Core Facility of IMB, Academia Sinica (AS-CFII-113-A1) for the EIIa-Cre mice and the Data Science Statistical Cooperation Center of Academia Sinica (AS-CFII-111-215) for statistical support. Finally, we would like to thank Drs. Li-Hao Cheng, Chih-Chieh Hsu and Shih-Hsuan Cheng for their helpful discussions and comments.

Disclosure statement

C.-M.C., and C.-C.W. were employed by Bened Biomedical Co., Ltd. at the time of the study. Y.-C.T. serves as a consultant and owns stock in Bened Biomedical Co., Ltd. None of the other authors had any personal or financial conflict of interest. The funder had no role in the design of the study; in the collection, analysis, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results.

Data availability statement

The data supporting the findings of this study are available within the article and its supplementary materials. The raw sequencing data for all 61 samples are deposited on Figshare https://figshare.com/s/6e1b71b946d8f74a7505.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2024.2359501

Additional information

Funding

This work was supported by the Industry-Academia Cooperation Project of Academia Sinica, the Brain Research Center under the Higher Education Sprout Project, co-funded by the Ministry of Education, and the National Science and Technology Council in Taiwan to S.-L.C. and the fund of the Research and Development Department of Bened Biomedical to C.-M.C.