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

Zhi-Xiang Xu, Ji-Wei Tan, Haifei Xu, Cassandra J. Hill, Olga Ostrovskaya, Kirill A. Martemyanov and Baoji Xu ()
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Zhi-Xiang Xu: The Scripps Research Institute Florida
Ji-Wei Tan: The Scripps Research Institute Florida
Haifei Xu: The Scripps Research Institute Florida
Cassandra J. Hill: The Scripps Research Institute Florida
Olga Ostrovskaya: The Scripps Research Institute Florida
Kirill A. Martemyanov: The Scripps Research Institute Florida
Baoji Xu: The Scripps Research Institute Florida

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11575-1

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