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 journalArticle

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.

LanguageEnglish (US)
PagesE9707-E9716
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number41
DOIs
StatePublished - Oct 9 2018

Fingerprint

Autophagy
Fragile X Syndrome
Neuronal Plasticity
Raptors
Cognition
Spine
Fragile X Mental Retardation Protein
Neurons
Lentivirus
Dendritic Spines
Recycling
Autistic Disorder
Lysosomes
Intellectual Disability
Small Interfering RNA
Proteolysis
Biomarkers
Phenotype

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice. / Yan, Jingqi; Porch, Morgan W.; Court-Vazquez, Brenda; Bennett, Michael V. L.; Zukin, R. Suzanne.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 41, 09.10.2018, p. E9707-E9716.

Research output: Contribution to journalArticle

@article{6a48058484bf424e822c1bde39d33006,
title = "Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice",
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.",
keywords = "Autism, Autophagy, Cognition, Fragile X syndrome, MTOR",
author = "Jingqi Yan and Porch, {Morgan W.} and Brenda Court-Vazquez and Bennett, {Michael V. L.} and Zukin, {R. Suzanne}",
year = "2018",
month = "10",
day = "9",
doi = "10.1073/pnas.1808247115",
language = "English (US)",
volume = "115",
pages = "E9707--E9716",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "41",

}

TY - JOUR

T1 - Activation of autophagy rescues synaptic and cognitive deficits in fragile X mice

AU - Yan, Jingqi

AU - Porch, Morgan W.

AU - Court-Vazquez, Brenda

AU - Bennett, Michael V. L.

AU - Zukin, R. Suzanne

PY - 2018/10/9

Y1 - 2018/10/9

N2 - 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.

AB - 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.

KW - Autism

KW - Autophagy

KW - Cognition

KW - Fragile X syndrome

KW - MTOR

UR - http://www.scopus.com/inward/record.url?scp=85054738281&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054738281&partnerID=8YFLogxK

U2 - 10.1073/pnas.1808247115

DO - 10.1073/pnas.1808247115

M3 - Article

VL - 115

SP - E9707-E9716

JO - Proceedings of the National Academy of Sciences of the United States of America

T2 - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 41

ER -