Journal of Brain Research

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Heterozygote Shank3b Mice Exhibit Sex-Dependent Changes In Proteins Required For Excitatory/Inhibitory Balance

Sophie Gregoretti, Anjali Kunnatha, Lil Gehner, Mykle Williams, Casey Rice, Beck Littlehale, Grace Phillips, Kylie Roach, Rebecca Harshman, Lyric Freeman, Lila McMaster, Laila James, Nadia Small, Erika Vargo, Stacey B.B. Dutton and Jennifer L. Larimore*

DOI: 10.37421/2684-4583.2025.8.303

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Altered expression of SHANK3 proteins has been implicated in multiple neurodevelopmental disorders, including Phelan-McDermid syndrome (PMS), schizophrenia (SZ), and autism spectrum disorders (ASDs). SHANK3B is a postsynaptic density protein that physically links ionotropic NMDA receptors to metabotropic mGlu5 receptors through interactions with scaffolding proteins, a connection essential for long-term potentiation. Previous studies have demonstrated that endosomal trafficking within dendritic spines regulates receptor insertion and recycling, processes fundamental to maintaining excitatory/inhibitory (E/I) balance. Here, we investigated endosomal protein expression and E/I regulatory proteins in a SHANK3B mouse model to better understand sex-dependent contributions to neurodevelopment. Using immunoblotting and immunohistochemistry, we identified sex-specific alterations in hippocampal expression of endosomal trafficking proteins and E/I markers. These findings represent a novel dimension of SHANK3B-related pathology. To assess behavioral relevance, we paired these molecular analyses with the open field test, the forced swim test, and seizure induction assays. Notably, we observed no significant behavioral differences between groups. Together, these results suggest that sex-dependent molecular alterations in endosomal and E/I pathways occur in SHANK3B mice in the absence of overt behavioral phenotypes. These findings advance our understanding of how SHANK3B deficiency shapes neurodevelopmental processes and highlight the importance of incorporating sex as a biological variable in studies of synaptic dysfunction.