Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice

Jingqi Yan, Morgan W. Porch, Brenda Court-Vazquez, Michael V.L. Bennett, R. Suzanne Zukin

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Fragile X syndrome (FXS) is the most frequent form of heritable intellectual disability and autism. Fragile X (Fmr1-KO) mice exhibit aberrant dendritic spine structure, synaptic plasticity, and cognition. Autophagy is a catabolic process of programmed degradation and recycling of proteins and cellular components via the lysosomal pathway. However, a role for autophagy in the pathophysiology of FXS is, as yet, unclear. Here we show that autophagic flux, a functional readout of autophagy, and biochemical markers of autophagy are down-regulated in hippocampal neurons of fragile X mice. We further show that enhanced activity of mammalian target of rapamycin complex 1 (mTORC1) and translocation of Raptor, a defining component of mTORC1, to the lysosome are causally related to reduced autophagy. Activation of autophagy by delivery of shRNA to Raptor directly into the CA1 of living mice via the lentivirus expression system largely corrects aberrant spine structure, synaptic plasticity, and cognition in fragile X mice. Postsynaptic density protein (PSD-95) and activity-regulated cytoskeletal-associated protein (Arc/Arg3.1), proteins implicated in spine structure and synaptic plasticity, respectively, are elevated in neurons lacking fragile X mental retardation protein. Activation of autophagy corrects PSD-95 and Arc abundance, identifying a potential mechanism by which impaired autophagy is causally related to the fragile X phenotype and revealing a previously unappreciated role for autophagy in the synaptic and cognitive deficits associated with fragile X syndrome.

Original languageEnglish (US)
Pages (from-to)E9707-E9716
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number41
DOIs
StatePublished - Oct 9 2018

Keywords

  • Autism
  • Autophagy
  • Cognition
  • Fragile X syndrome
  • MTOR

ASJC Scopus subject areas

  • General

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