Follistatin mediates learning and synaptic plasticity via regulation of Asic4 expression in the hippocampus.

The biological mechanisms underpinning learning are unclear. Mounting evidence has suggested that adult hippocampal neurogenesis is involved although a causal relationship has not been well defined. Here, using high-resolution genetic mapping of adult neurogenesis, combined with sequencing information, we identify follistatin () and demonstrate its involvement in learning and adult neurogenesis. We confirmed that brain-specific knockout (KO) mice exhibited decreased hippocampal neurogenesis and demonstrated that FST is critical for learning. KO mice exhibit deficits in spatial learning, working memory, and long-term potentiation (LTP). In contrast, hippocampal overexpression of in KO mice reversed these impairments. By utilizing RNA sequencing and chromatin immunoprecipitation, we identified as a target gene regulated by FST and show that plays a critical role in learning deficits caused by deletion. Long-term overexpression of hippocampal in C57BL/6 wild-type mice alleviates age-related decline in cognition, neurogenesis, and LTP. Collectively, our study reveals the functions for FST in adult neurogenesis and learning behaviors.