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

Abstract

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 (<i>Fst</i>) and demonstrate its involvement in learning and adult neurogenesis. We confirmed that brain-specific <i>Fst</i> knockout (KO) mice exhibited decreased hippocampal neurogenesis and demonstrated that FST is critical for learning. <i>Fst</i> KO mice exhibit deficits in spatial learning, working memory, and long-term potentiation (LTP). In contrast, hippocampal overexpression of <i>Fst</i> in KO mice reversed these impairments. By utilizing RNA sequencing and chromatin immunoprecipitation, we identified <i>Asic4</i> as a target gene regulated by FST and show that <i>Asic4</i> plays a critical role in learning deficits caused by <i>Fst</i> deletion. Long-term overexpression of hippocampal <i>Fst</i> 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.