Early-Life High-Fat Diet Impairs Autophagy and Reduces GABAA Receptor Expression in Hypothalamic Neurons, Promoting Depressive-like Behaviors in Offspring Mice

Backgrounds: Early-life nutritional excess increases the risk of depressive-like phenotypes in offspring, yet the underlying mechanisms remain unclear. This study investigated whether perinatal and adolescent high-fat diet (HFD) exposure is associated with depressive-like behaviors through disruption of the autophagy–GABARAP pathway in hypothalamic neurons. Methods: A mouse model of HFD exposure during both periods was established. Depressive-like behaviors, hypothalamic autophagic flux, and GABARAP–GABAAR co-localization were assessed. Primary hypothalamic neuronal cultures were treated with rapamycin. RNA sequencing and co-immunoprecipitation were performed to identify transcriptional changes and protein–protein interactions. Results: HFD exposure induced metabolic disturbances and depressive-like behaviors, suppressed autophagic flux (p62 and LC3-II accumulation), increased GABARAP–GABAAR co-localization, and reduced GABAAR protein abundance with elevated hypothalamic neuronal activity. Rapamycin reversed these alterations in primary neurons. RNA sequencing identified 87 differentially expressed genes (e.g., upregulated Plin4, Txnip; downregulated Npas4, Avp), while GABA receptor subunits and core autophagy genes remained unchanged at the transcriptional level. Enrichment analyses linked differentially expressed genes to mitophagy, oxidative phosphorylation, and the ubiquitin–proteasome system, with downregulated neuronal pathways. Co-immunoprecipitation confirmed direct GABARAP–GABAAR interaction. Conclusions: Impaired autophagic flux correlates with reduced GABAAR protein levels and increased hypothalamic neuronal activity, suggesting a link between autophagy–GABARAP dysregulation and depressive-like behaviors. The autophagy–GABARAP axis, together with transcriptomic reprogramming, may represent a key link between early-life nutritional excess and offspring depressive-like phenotypes, warranting further investigation as an intervention target.