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

Kwan Young Lee, Jiuhe Zhu, Cathryn A Cutia, Catherine A Christian‐Hinman, Justin S Rhodes, Nien‐Pei Tsai

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish (US)
Article numbere52645
JournalEMBO Reports
DOIs
StateAccepted/In press - Aug 3 2021

Keywords

  • cofilin
  • synaptic plasticity
  • Nedd4-2
  • infantile spasm
  • hippocampus-dependent learning

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Biochemistry

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