| 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 (Fst) and demonstrate its involvement in learning and adult neurogenesis. We confirmed that brain-specific Fst knockout (KO) mice exhibited decreased hippocampal neurogenesis and demonstrated that FST is critical for learning. Fst KO mice exhibit deficits in spatial learning, working memory, and long-term potentiation (LTP). In contrast, hippocampal overexpression of Fst in KO mice reversed these impairments. By utilizing RNA sequencing and chromatin immunoprecipitation, we identified Asic4 as a target gene regulated by FST and show that Asic4 plays a critical role in learning deficits caused by Fst deletion. Long-term overexpression of hippocampal Fst 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.A wide variety of human disorders such as intellectual disability feature impairment of learning and memory. These conditions have a profound impact on quality of life and social functioning. Despite this, the biological mechanisms underpinning learning are not yet fully understood. However, mounting evidence has suggested that hippocampal neurogenesis is involved (1). Several publications report learning or emotional phenotypes in rodent models, which have little or no neurogenesis in adulthood (2–5), although these, and other findings, have been questioned (6). Despite the lack of consensus on the causal relationship about adult hippocampal neurogenesis on learning, it is possible that the same genes affect both neurogenesis and learning. Indeed, in mouse inbred strains, neurogenesis is genetically correlated with performance in spatial learning and memory tasks (7, 8), and spatial memory in rats is related to the levels of hippocampal neurogenesis (9).We hypothesized that one way to identify genes that influence learning is to identify those that contribute to heritable variation in neurogenesis (10). In this study, we used genetic mapping data from heterogeneous stock (HS) mice to identify loci associated with neurogenesis (11). We increased mapping resolution further by the incorporation of sequence information. This technique has been shown to increase mapping resolution to the point of identifying causal variants (12). One of the target genes, Fst, is predominantly expressed in the cortex, olfactory bulb, and dentate gyrus. Interestingly, two of these regions are where adult neurogenesis occurs. Fst is known to encode the protein follistatin (FST), an activin-binding protein (13, 14), which neutralizes activin bioactivity (15). FST also binds to other members of the transforming growth factor-β superfamily but with a 10-fold lower affinity than for activin A (16). In the brain, activin has been shown to play a role in the maintenance of long-term memory (17). Despite numerous studies about the functions of FST in regulation of muscle growth (18) and energy metabolism (19), its roles in the brain are still unknown.In this study, we used brain-specific Fst knockout (KO) mice to confirm its effect on neurogenesis, and we identified learning deficits in the Fst KO mice as well as deficits in long-term potentiation (LTP) through the regulation of acid-sensing ion channel 4 (ASIC4). Our study demonstrates the power of combining genetic mapping with functional work, and we provide insights into the role of FST in the hippocampus and its influence on learning. |
