Caspase-2 promotes AMPA receptor internalization and cognitive flexibility via mTORC2-AKT-GSK3β signaling

Nat Commun. 2019 Aug 9;10(1):3622. doi: 10.1038/s41467-019-11575-1.


Caspase-2 is the most evolutionarily conserved member in the caspase family of proteases and is constitutively expressed in most cell types including neurons; however, its physiological function remains largely unknown. Here we report that caspase-2 plays a critical role in synaptic plasticity and cognitive flexibility. We found that caspase-2 deficiency led to deficits in dendritic spine pruning, internalization of AMPA receptors and long-term depression. Our results indicate that caspase-2 degrades Rictor, a key mTOR complex 2 (mTORC2) component, to inhibit Akt activation, which leads to enhancement of the GSK3β activity and thereby long-term depression. Furthermore, we found that mice lacking caspase-2 displayed elevated levels of anxiety, impairment in reversal water maze learning, and little memory loss over time. These results not only uncover a caspase-2-mTORC2-Akt-GSK3β signaling pathway, but also suggest that caspase-2 is important for memory erasing and normal behaviors by regulating synaptic number and transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety
  • Behavior, Animal
  • Carrier Proteins / metabolism
  • Caspase 2 / genetics
  • Caspase 2 / metabolism*
  • Cognition / physiology*
  • Dendritic Spines / genetics
  • Dendritic Spines / metabolism
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Hippocampus / metabolism
  • Long-Term Synaptic Depression / genetics
  • Long-Term Synaptic Depression / physiology
  • Male
  • Maze Learning
  • Mechanistic Target of Rapamycin Complex 2 / metabolism*
  • Memory Disorders / metabolism
  • Mice
  • Mice, Knockout
  • Neuronal Plasticity
  • Neurons / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptors, AMPA / metabolism*
  • Receptors, Glutamate / metabolism
  • Signal Transduction / physiology*


  • Carrier Proteins
  • Receptors, AMPA
  • Receptors, Glutamate
  • Glycogen Synthase Kinase 3 beta
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • Casp2 protein, mouse
  • Caspase 2