CaMKIIα‐TARPγ8 signaling mediates hippocampal synaptic impairment in aging

JianHua, Zhao; Li, MingCan; Hu, Qilin; Donoghue, Peter; Jiang, Sanwei; Li, Junmei; Li, Songji; Ren, Xinyi; Zhang, Ziyuan; Du, Jingzhi; Yu, Yi; Chazot, Paul; Lu, Chengbiao

Abstract

Aging‐related decline in memory and synaptic function are associated with the dysregulation of calcium homeostasis, attributed to the overexpression of voltage‐gated calcium channels (VGCC). The membrane insertion of AMPAR governed by the AMPAR auxiliary proteins is essential for synaptic transmission and plasticity (LTP). In this study, we demonstrated the hippocampal expression of the transmembrane AMPAR regulatory proteins γ‐8 (TARPγ8) was reduced in aged mice along with the reduced CaMKIIα activity and memory impairment. We further showed that TARPγ8 expression was dependent on CaMKIIα activity. Inhibition of CaMKIIα activity significantly reduced the hippocampal TARPγ8 expression and CA3‐CA1 LTP in young mice to a similar level to that of the aged mice. Furthermore, the knockdown of hippocampal TARPγ8 impaired LTP and memory in young mice, which mimicked the aging‐related changes. We confirmed the enhanced hippocampal VGCC (Cav‐1.3) expression in aged mice and found that inhibition of VGCC activity largely increased both p‐CaMKIIα and TARPγ8 expression in aged mice, whereas inhibition of NMDAR or Calpains had no effect. In addition, we found that the exogenous expression of human TARPγ8 in the hippocampus in aged mice restored LTP and memory function. Collectively, these results indicate that the synaptic and cognitive impairment in aging is associated with the downregulation of CaMKIIα‐TARPγ8 signaling caused by VGCC activation. Our results suggest that TARPγ8 may be a key molecular biomarker for brain aging and that boosting CaMKIIα‐TARPγ8 signaling may be critical for the restoration of synaptic plasticity of aging and aging‐related diseases.

Citation

JianHua, Z., Li, M., Hu, Q., Donoghue, P., Jiang, S., Li, J., Li, S., Ren, X., Zhang, Z., Du, J., Yu, Y., Chazot, P., & Lu, C. (online). CaMKIIα‐TARPγ8 signaling mediates hippocampal synaptic impairment in aging. Aging Cell, Article e14349. https://doi.org/10.1111/acel.14349

• Journal Article Type: Article
• Acceptance Date: Sep 5, 2024
• Online Publication Date: Oct 8, 2024
• Deposit Date: Oct 23, 2024
• Publicly Available Date: Oct 23, 2024
• Journal: Aging Cell
• Print ISSN: 1474-9718
• Electronic ISSN: 1474-9726
• Publisher: Anatomical Society of Great Britain and Ireland
• Peer Reviewed: Peer Reviewed
• Article Number: e14349
• DOI: https://doi.org/10.1111/acel.14349
• Keywords: hippocampus, TARPγ8, CaMKIIα, VGCC, LTP, aging
• Public URL: https://durham-repository.worktribe.com/output/2954969