biostudies-literatureXu ZXNIDA NIH HHSNIDDK NIH HHSNIMH NIH HHSNINDS NIH HHSU.S. Department of Health & Human Services | National Institutes of Health3622https://www.ebi.ac.uk/biostudies/studies/S-EPMC6689033biostudies-literatureUnknown10(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, andNature communicationsCaspase-2 promotes AMPA receptor internalization and cognitive flexibility via mTORC2-AKT-GSK3β signaling.PMC6689033R01 NS073930DK103335R01 DK105954MH105482R01 DK103335DK105954NS073930R01 MH105482K02 DA026405Martemyanov KAXu BHill CJXu ZXTan JWXu HOstrovskaya OfalseCaspase-2 promotes AMPA receptor internalization and cognitive flexibility via mTORC2-AKT-GSK3β signaling.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, and2019-01-01T00:00:00Z2019 Aug2025-04-29T11:06:03.077Z2019-08-16T07:02:27ZS-EPMC66890333139958410.1038/s41467-019-11575-1