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

Proc Natl Acad Sci U S A. 2021 Sep 28;118(39):e2109040118. doi: 10.1073/pnas.2109040118.

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.

Keywords: Asic4; adult neurogenesis; follistatin; hippocampus; learning.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Sensing Ion Channels / genetics
  • Acid Sensing Ion Channels / metabolism*
  • Animals
  • Cognition
  • Female
  • Follistatin / physiology*
  • Hippocampus / metabolism*
  • Long-Term Potentiation
  • Male
  • Memory
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurogenesis*
  • Neuronal Plasticity*
  • Spatial Learning / physiology*
  • Synapses / physiology

Substances

  • ASIC4 protein, mouse
  • Acid Sensing Ion Channels
  • Follistatin