Major Depressive Disorder (MDD) is a prevalent global cause of disability, affecting approximately 5% of adults, and has a higher incidence in females. Despite its significant impact, its diverse symptoms and causes lack clear identification, hindering effective treatments. Understanding the underlying mechanisms is crucial. Studies in various brain areas indicate an astrocyte pathology in MDD, revealing reduced numbers and altered morphology, gene, and protein expression. Astrocytes influence synapse remodeling, crucial for neuronal network maturation. Notably, their phagocytic ability, facilitated by the Multiple EGF-like Domains 10 (MEGF10) signaling pathway, eliminates synapses and debris. Abnormal synapse elimination in MDD may disrupt neuronal network balance fostering the onset of disease symptoms. Astrocytes can remodel synapses, promoting their formation or pruning, especially during developmental stages, but also in adulthood. We hypothesize that disrupted MEGF10 expression and subcellular localization in MDD lead to a non-functional protein differently affecting males and females, causing a synapse formation/elimination imbalance. Our study aims to assess whether MEGF10 alterations are linked to depressive-like behavior in animal models and if there are sex-dependent differences. Evaluation includes measuring MEGF10 expression, astrocytic synaptic engulfment capability, and MEGF10 subcellular localization using Immunohistochemistry and Immunocytochemistry in the different disease animal models and with both sexes. While there were no changes in expression, disease models exhibited reduced colocalization of MEGF10 with lipid rafts and decreased engulfing capacity. This suggests that MEGF10 could be a novel potential therapeutic target for developing strategies to address MDD.