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

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.