Basic Science and Pathogenesis.

Background: Sorbs2 is a cytoskeletal adaptor protein that is expressed in hippocampal neurons, but its mechanistic role in these cells is not yet fully understood.

Method: We created two groups of mice for our study: whole-body Sorbs2-Knockout (KO) mice and Sorbs2-Flox mice, which had neuronal knockout via AAV-PHP.eB-hSyn1-Cre virus injection. We assayed mixed-sex littermate cohorts at 6 months of age (n = 24 each, WT/KO; n = 8 each ± CRE) with behavior tests. We used postmortem brain samples to visualize and quantify Sorbs2 expression and microtubule stability.

Result: Our preliminary results suggest that female Sorbs2-KO mice have a decrease in freezing time during contextual fear conditioning at 6 months of age. We next tested an independent cohort of females (n = 8v8) and the data show reduced freezing time in cued fear conditioning and decreased interaction time with the displaced object in Spatial Object Recognition tests after 24 hours. From the above-mentioned experiments, we have collected tissue samples for molecular and histological analysis. Preliminary results show that global Sorbs2-KO mice have a complete loss of an immunoreactive band specific to neuronal Sorbs2 isoform at ∼150 kDa, whereas AAV-Cre injected Sorbs2-flox mice have > 50% reduction in neuronal Sorbs2. In preliminary studies, we assessed microtubule stability in hippocampus homogenates from global Sorbs2-KO or WT mice and showed an increase in the amount of free tubulin and a decrease in the amount of polymerized tubulin in the knockout samples. These data suggest that loss of Sorbs2 may destabilize microtubules in the hippocampus.

Conclusion: Our results suggest that Sorbs2 may regulate microtubule stability in the brain and be involved in memory formation or retrieval. In future studies, we plan to identify populations of Sorbs2-expressing cells in the brain, interrogate neuronal-specific Sorbs2 deletion, and assess the intersection between Sorbs2 and AD-related phenotypes in mouse models of neurodegeneration.