Caveolin-1-Mediated Cholesterol Accumulation Contributes to Exaggerated mGluR-Dependent Long-Term Depression and Impaired Cognition in Fmr1 Knockout Mice

Mol Neurobiol. 2023 Jun;60(6):3379-3395. doi: 10.1007/s12035-023-03269-z. Epub 2023 Mar 1.


Fragile X syndrome (FXS) is one of the most common inherited mental retardation diseases and is caused by the loss of fragile X mental retardation protein (FMRP) expression. The metabotropic glutamate receptor (mGluR) theory of FXS states that enhanced mGluR-dependent long-term depression (LTD) due to FMRP loss is involved in aberrant synaptic plasticity and autistic-like behaviors, but little is known about the underlying molecular mechanism. Here, we found that only hippocampal mGluR-LTD was exaggerated in adolescent Fmr1 KO mice, while N-methyl-D-aspartate receptor (NMDAR)-LTD was intact in mice of all ages. This development-dependent alteration was related to the differential expression of caveolin-1 (Cav1), which is essential for caveolae formation. Knockdown of Cav1 restored the enhanced mGluR-LTD in Fmr1 KO mice. Moreover, hippocampal Cav1 expression in Fmr1 KO mice induced excessive endocytosis of the α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) receptor subunit GluA2. This process relied on mGluR1/5 activation rather than NMDAR. Interference with Cav1 expression reversed these changes. Furthermore, massive cholesterol accumulation contributed to redundant caveolae formation, which provided the platform for mGluR-triggered Cav1 coupling to GluA2. Importantly, injection of the cholesterol scavenger methyl-β-cyclodextrin (Mβ-CD) recovered AMPA receptor trafficking and markedly alleviated hyperactivity, hippocampus-dependent fear memory, and spatial memory defects in Fmr1 KO mice. Together, our findings elucidate the important role of Cav1 in mediating mGluR-LTD enhancement and further inducing AMPA receptor endocytosis and suggest that cholesterol depletion by Mβ-CD during caveolae formation may be a novel and safe strategy to treat FXS.

Keywords: Caveolin-l; Cholesterol; Endocytosis; Fragile X syndrome; Long-term depression; Metabotropic glutamate receptor.

MeSH terms

  • Animals
  • Caveolin 1 / metabolism
  • Cognition
  • Depression
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome* / metabolism
  • Hippocampus / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuronal Plasticity
  • Receptors, AMPA / metabolism
  • Receptors, Metabotropic Glutamate* / metabolism


  • Caveolin 1
  • Receptors, AMPA
  • Fragile X Mental Retardation Protein
  • Receptors, Metabotropic Glutamate
  • Fmr1 protein, mouse