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Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer’s disease

Neuropsychopharmacology volume 49, pages 942–952 (2024)Cite this article

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Abstract

Cognitive deterioration and memory decline associated with the progression of Alzheimer’s disease (AD) primarily results from synaptic failure. However, current understanding of the upstream regulatory mechanisms controlling synaptic plasticity remains limited. Salt-inducible kinase 3 (SIK3) is central to the signal pathway and is involved in neuronal regulation of sleep duration in mice. We speculated that the SIK3 cascade signaling pathway might contribute to the pathogenesis of AD. Thus, the present study employed AD transgenic mouse models, Morris Water Maze, virus-mediated gene transfer, electrophysiology, co-immunoprecipitation, western blotting, quantitative polymerase chain reaction, immunofluorescence, ChIP-qPCR, Golgi-Cox staining and dendritic spine analysis to investigate this connection. Our results revealed that SIK3 mRNA/protein expression was significantly reduced in middle-aged AD transgenic mouse models and AD patients. Conditional deletion of SIK3 gene in dorsal hippocampal neurons of 5×FAD mice further accelerated cognitive deterioration and impaired synaptic plasticity. In hippocampal neuronal cultures, SIK3 formed a complex with HDAC4, directly phosphorylated HDAC4 and regulated its nuclear cytoplasmic shuttle. Overexpression of SIK3 could facilitate the expression of synaptic plasticity-related genes by directly repressing mef2c or involving the recruitment of histone deacetylase to promoter regions of target genes through regulation of p-HDAC4, and vice versa. Moreover, up-regulation of SLP-S, the truncated fragment of SIK3, in dorsal hippocampal neurons, restored the synaptic plasticity and alleviates the cognitive impairment in 5×FAD mice. Collectively, these findings revealed a novel and important role of SIK3-HDAC4 regulation of synaptic plasticity and propose a new target for therapeutic approaches of cognitive deficits associated with AD.

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Fig. 1: SIK3 expression decreases in the middle-aged AD transgenic mouse models and AD patients.
Fig. 2: Conditional deletion of SIK3 in dorsal hippocampus impairs cognitive function and synaptic plasticity in 5×FAD mice.
Fig. 3: SIK3 forms a complex with HDAC4 to regulate its nucleocytoplasmic shuttling.
Fig. 4: HDAC4 regulates the transcription of genes related to synaptic plasticity through mef2c and histone acetylation.
Fig. 5: The SLP-S upregulation restores the synaptic plasticity and alleviates the cognitive impairment in 5×FAD mice.

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Data availability

The authors declare that all data supporting the findings of this study are available in this article and its Supplementary information files. Further inquiries can be directed to the corresponding author.

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Acknowledgements

We thank Professor Qinghua Liu from National Institute of Biological Sciences, Beijing, China for providing the SLP-S plasmid. We thank Guanghao Liu from Department of Bioinformatics, Fujian Medical University for bioinformation analysis.

Funding

This work was supported by grants to Xiaoman Dai from the National Natural Science Foundation of China (No.82101481), the Excellent Young Scholars Cultivation Project of Fujian Medical University Union Hospital (No.2022XH032), the Health and Family Planning Commission of Fujian Province (No.2021GGA012), the Science and Technology Program of Fujian Province (No. 2022J01250). This work was also supported by grants to Xiaochun Chen from the National Natural Science Foundation of China (No. U21A20362).

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  1. These authors contributed equally: Xiaoman Dai, Anlan Lin.

Authors and Affiliations

  1. Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, Fujian, 350001, China

    Xiaoman Dai, Lvping Zhuang, Qingyong Zeng, Lili Cai & Xiaochun Chen

  2. Fujian Key Laboratory of Molecular Neurology, Fujian Key Laboratory of Vascular Aging, School of Basic Medical Sciences, Fujian Medical University, 88 Jiaotong Road, Fuzhou, Fujian, 350001, China

    Xiaoman Dai, Anlan Lin, Yuanxiang Wei, Hongjie Liang, Weijie Gao, Jing Zhang & Xiaochun Chen

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Contributions

XD performed the experiments and wrote the manuscript; AL performed electrophysiological recording of brain slices and data analysis; LZ designed and validated viruses. QZ performed the breeding of mice; LC, YW, HL, and WG completed virus injection, animal behavior and behavioral analysis; JZ and XC conceived and designed the project, and prepared and revised the manuscript; all authors read and commented on the manuscript.

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Correspondence to Jing Zhang or Xiaochun Chen.

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Dai, X., Lin, A., Zhuang, L. et al. Targeting SIK3 to modulate hippocampal synaptic plasticity and cognitive function by regulating the transcription of HDAC4 in a mouse model of Alzheimer’s disease. Neuropsychopharmacol. 49, 942–952 (2024). https://doi.org/10.1038/s41386-023-01775-1

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