Astrocytic gatekeeping of neural circuitry and synaptic balance in an autism mouse model: mechanistic insights beyond Gryllus bimaculatus extract-derived therapy

Background: Autism spectrum disorder (ASD) is characterized by impaired synaptic development and disrupted excitation/inhibition (E/I) balance. While neuronal mechanisms have been extensively studied, accumulating evidence indicates that glial cells—particularly astrocytes—play a crucial role in maintaining synaptic homeostasis and regulating neurotransmission during brain development. However, the functional contribution of astrocytes to ASD pathogenesis remains insufficiently defined. Methods: This study aimed to explore astrocyte-mediated regulation of E/I balance in ASD using Gryllus bimaculatus (Gb) extract as a neuroprotective biological probe. A valproic acid (VPA)-induced ASD mouse model was established, and glial-neuronal interactions were assessed through analyses of neural progenitor cells, primary cortical neurons, astrocytes, and neuron-astrocyte co-cultures. Results: Gb extract reversed VPA-induced alterations in neural progenitor proliferation and differentiation and restored expression of key synaptic proteins (neuroligins, neurexin, synaptophysin). Notably, astrocyte-specific markers (GFAP, EAAT1/2) and E/I-related transporters (vGluT1, VGAT, GABA R1α, NMDA R1) were dysregulated in the ASD model and normalized by Gb treatment. Co-culture experiments demonstrated that astrocytes from VPA-treated animals, rather than neurons alone, were primarily responsible for E/I imbalance and synaptic abnormalities. Gb extract acted as a modulator of astrocytic function, restoring synaptic integrity and neurodevelopmental stability. Conclusion: Our findings underscore the pivotal role of astrocytes in the development and modulation of ASD-related synaptic pathology. Gb extract served as a valuable biological tool to reveal glial contributions to synaptic regulation and E/I balance. These insights support targeting astrocytic pathways with Gb extract as a novel therapeutic strategy for ASD.