Abstract
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.
Highlights
Caspase-2 is the most evolutionarily conserved member in the caspase family of proteases and is constitutively expressed in most cell types including neurons; its physiological function remains largely unknown
We have found that caspase-2 inhibits mTORC2induced Akt activation by cleaving the mTOR complex 2 (mTORC2) scaffold protein Rictor, thereby stimulating the activity of glycogen synthase kinase 3β (GSK3β) and promoting long-term depression (LTD)
To test whether caspase-2 plays a role in synapse pruning, we applied the inhibitor Z-VDVAD-FMK to primary hippocampal neuronal cultures that had been in vitro for 21 days (DIV21), examined the density and diameter of dendritic spines on DIV28
Summary
Caspase-2 is the most evolutionarily conserved member in the caspase family of proteases and is constitutively expressed in most cell types including neurons; its physiological function remains largely unknown. Several molecules, including major histocompatibility class I molecules and the precursor of brain-derived neurotrophic factor, have been found to be essential for both synapse pruning and long-term depression (LTD), which refers to enduring decrease of synaptic strength[14,15,16,17,18,19]. Long-term potentiation (LTP) refers to enduring increase in synaptic strength and is the opposing process to LTD This bidirectional synaptic plasticity is believed to be critically important in enabling the brain to store vast amounts of information[21,22]. The mTORC2 activity is necessary for late-phase LTP27 and hippocampal mGluR-dependent LTD28 It is unclear which upstream signaling pathway regulates the activity of mTORC2 to mediate expression of both
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
