Infantile spasms-linked Nedd4-2 mediates hippocampal plasticity and learning via cofilin signaling

EMBO Rep. 2021 Oct 5;22(10):e52645. doi: 10.15252/embr.202152645. Epub 2021 Aug 3.


Individuals affected by infantile spasms (IS), such as those carrying mutations in an IS-linked gene, neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4-2), exhibit developmental delays and learning disabilities, but the underlying mechanism is unknown. Using conditional Nedd4-2 knockout mice, we uncover that Nedd4-2 functions to maintain the excitatory synapses in hippocampal neurons and allows for late-phase long-term synaptic potentiation (L-LTP) at Schaffer collateral synapses in the hippocampus. We also find that Nedd4-2 is required for multiple forms of hippocampus-dependent learning and memory. Mechanistically, we show that loss of Nedd4-2 leads to a decrease in actin polymerization caused by reduced phosphorylation of the actin depolymerizing protein cofilin. A cell-permeable peptide promoting phosphorylation of endogenous cofilin in Nedd4-2 knockout neurons restores the number of hippocampal excitatory synapses and hippocampal L-LTP and partially restores hippocampus-dependent learning in mice. Taken together, our results reveal a novel mechanism underlying IS-associated learning disabilities and may provide information for future therapeutic strategies for IS.

Keywords: Nedd4-2; cofilin; hippocampus-dependent learning; infantile spasm; synaptic plasticity.

Publication types

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

MeSH terms

  • Actin Depolymerizing Factors* / metabolism
  • Animals
  • Disease Models, Animal
  • Hippocampus / metabolism
  • Humans
  • Infant
  • Learning
  • Long-Term Potentiation
  • Mice
  • Neuronal Plasticity
  • Spasms, Infantile* / genetics
  • Synapses / metabolism


  • Actin Depolymerizing Factors