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Astragaloside IV improves autism-like behaviors in BTBR mice by modulating CAMK2N2-dependent OXPHOS and neurotransmission in the mPFC

ABSTRACT: Autism spectrum disorder (ASD) represents a multifaceted set of neurodevelopmental conditions marked by challenges with social interaction and communication, restricted and repetitive behavior. Astragaloside IV (ASIV), a natural compound derived from the traditional Chinese herb Astragalus membranaceus, exhibits robust neuroprotective effects. However, whether ASIV can ameliorate behavioral deficits in ASD remains unknown. The present study found that ASIV treatment significantly reduced social deficits and repetitive behaviors in the BTBR T+tf/J (BTBR) mouse model of autism in a dose-dependent manner. The ASIV treatment normalized the neurotransmitter levels (GABA and glutamate) and their corresponding vesicular transporters (vGAT, vGlut1) in the medial prefrontal cortex (mPFC). Furthermore, whole-cell patch-clamp recordings showed that the imbalance between excitatory and inhibitory synaptic transmission in layer V of mPFC was reversed after ASIV administration. Mechanistically, bulk RNA-seq and PPI network analysis identified the CAMK2N2 as the crucial bridging gene regulating both oxidative phosphorylation and neurotransmission. CAMK2N2 overexpression in the mPFC abolished the beneficial effects of ASIV on autistic symptoms in BTBR mice via the CAMK2/CREB pathway. These findings suggest that ASIV may serve as a promising therapeutic option for ASD and imply that the CAMK2N2/CAMK2/CREB axis could be a potential target for these patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE271821 | GEO | 2025/07/15

REPOSITORIES: GEO

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Project description:Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into 3 phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all 3 subgroups of ASD are 5 novel genes which appear to associate with androgen sensitivity, which may underlie the strong 4:1 bias towards affected males. Gene expression profiling of 116 LCL from autistic (87) and nonautistic (29) individuals were obtained using a custom-printed DNA microarray containing 39,936 elements (TIGR 40K Human array, GPL3427) and a reference design in which each sample was compared to the Stratagene Universal Human RNA standard. The 87 autistic samples were divided into phenotypic subgroups (language, mild, savant) on the basis of cluster analyses of scores from an autism diagnostic questionnaire, the Autism Diagnostic Interview-Revised instrument. Differentially expressed genes were determined for all autistic vs. control groups, as well as for each of 3 phenotypic ASD groups and controls.

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Astragaloside IV improves autism-like behaviors in BTBR mice by modulating CAMK2N2-dependent OXPHOS and neurotransmission in the mPFC

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