Cholesterol loss during glutamate-mediated excitotoxicity

EMBO J. 2012 Apr 4;31(7):1764-73. doi: 10.1038/emboj.2012.31. Epub 2012 Feb 17.


The deregulation of brain cholesterol metabolism is typical in acute neuronal injury (such as stroke, brain trauma and epileptic seizures) and chronic neurodegenerative diseases (Alzheimer's disease). Since both conditions are characterized by excessive stimulation of glutamate receptors, we have here investigated to which extent excitatory neurotransmission plays a role in brain cholesterol homeostasis. We show that a short (30 min) stimulation of glutamatergic neurotransmission induces a small but significant loss of membrane cholesterol, which is paralleled by release to the extracellular milieu of the metabolite 24S-hydroxycholesterol. Consistent with a cause-effect relationship, knockdown of the enzyme cholesterol 24-hydroxylase (CYP46A1) prevented glutamate-mediated cholesterol loss. Functionally, the loss of cholesterol modulates the magnitude of the depolarization-evoked calcium response. Mechanistically, glutamate-induced cholesterol loss requires high levels of intracellular Ca(2+), a functional stromal interaction molecule 2 (STIM2) and mobilization of CYP46A1 towards the plasma membrane. This study underscores the key role of excitatory neurotransmission in the control of membrane lipid composition, and consequently in neuronal membrane organization and function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium-Binding Proteins / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cholesterol / metabolism*
  • Cholesterol 24-Hydroxylase
  • Gene Knockdown Techniques
  • Glutamic Acid / metabolism*
  • Glutamic Acid / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Hydroxycholesterols / metabolism
  • Membrane Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Rats
  • Rats, Wistar
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism
  • Stromal Interaction Molecule 2
  • Synaptic Transmission*


  • Calcium-Binding Proteins
  • Hydroxycholesterols
  • Membrane Proteins
  • STIM2 protein, rat
  • Stromal Interaction Molecule 2
  • Glutamic Acid
  • 24-hydroxycholesterol
  • Cholesterol
  • Steroid Hydroxylases
  • Cholesterol 24-Hydroxylase
  • Calcium