Comprehensive behavioral phenotyping of male Septin 3-deficient mice reveals task-specific abnormalities

The septin cytoskeleton is recognized as the fourth component of the cytoskeleton. Septin 3 (SEPT3)/G-septin is a neuron-selective subunit of the septin family and is widely expressed in mature neurons. We previously demonstrated that SEPT3 regulates long-term potentiation (L-LTP)-dependent extension of smooth endoplasmic reticulum (sER) into dendritic spines of granule cells in the hippocampal dentate gyrus (DG), and that Sept3 knockout (Sept3^−/−) mice exhibited impairments in DG-dependent spatial long-term memory. However, the broader behavioral consequences of SEPT3 deficiency remain largely unexplored. To address this, we conducted comprehensive behavioral phenotyping of male Sept3^−/− mice using a standardized test battery. In the social interaction test in a novel environment, Sept3^−/− mice showed increased contact frequency and interaction time. In contrast, performance in the three-chamber social interaction test was comparable to wild-type mice, indicating context-dependent deficits. In contextual fear conditioning, Sept3^−/− mice displayed reduced freezing 24 h after training, but not 35 days later. In the T-maze forced alternation task, deficits were observed in choice accuracy and latency. These results demonstrate that Sept3^−/− mice exhibit selective behavioral impairments depending on task demands and environmental context. Our findings provide the first behavioral characterization of Sept3^−/− mice and offer new insights into the functional role of SEPT3, laying a foundation for future investigation into its molecular and circuit-level mechanisms.