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Distinct roles of astroglia and neurons in synaptic plasticity and memory

Molecular Psychiatry volume 27, pages 873–885 (2022)Cite this article

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Abstract

Long-term potentiation (LTP) in the hippocampus is the most studied form of synaptic plasticity. Temporal integration of synaptic inputs is essential in synaptic plasticity and is assumed to be achieved through Ca2+ signaling in neurons and astroglia. However, whether these two cell types play different roles in LTP remain unknown. Here, we found that through the integration of synaptic inputs, astrocyte inositol triphosphate (IP3) receptor type 2 (IP3R2)-dependent Ca2+ signaling was critical for late-phase LTP (L-LTP) but not early-phase LTP (E-LTP). Moreover, this process was mediated by astrocyte-derived brain-derived neurotrophic factor (BDNF). In contrast, neuron-derived BDNF was critical for both E-LTP and L-LTP. Importantly, the dynamic differences in BDNF secretion play a role in modulating distinct forms of LTP. Moreover, astrocyte- and neuron-derived BDNF exhibited different roles in memory. These observations enriched our knowledge of LTP and memory at the cellular level and implied distinct roles of astrocytes and neurons in information integration.

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Fig. 1: Astroglial IP3R2-dependent signaling is required for L-LTP.
Fig. 2: Astrocytic Ca2+ responses to HFS in IP3R2-KO and IP3R2-cKO mice and their WT mice.
Fig. 3: Astrocytic BDNF is required for L-LTP.
Fig. 4: Neuronal BDNF is critical for E-LTP and L-LTP.
Fig. 5: The dynamics of BDNF secretion are important in modulating distinct forms of LTP.
Fig. 6: Hippocampal-dependent learning and memory are differentially impaired among mice with manipulation in astroglia or neurons in the contextual fear conditioning test.

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Acknowledgements

We thank J. Chen (University of California, San Diego) for providing IP3R2+/− mice and P.G. Haydon (Tufts University School of Medicine, Boston) for providing GFAP-tTA and tetO.SNARE mouse lines. We also thank Dr. B.S. Khakh (University of California Los Angeles, Los Angeles) for providing GECIquant software. This work was supported by grants from the National Natural Science Foundation of China (82090032, 31830033, 31600864), the Program for Changjiang Scholars and Innovative Research Team in University (IRT_16R37), the Key-Area Research and Development Program of Guangdong Province (2018B030334001, 2018B030340001), the Science and Technology Program of Guangzhou (202007030013), Natural Science Foundation of Guangdong Province (2021A1515012181) and Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence Fund (2019020).

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  1. These authors contributed equally: Ji-Hong Liu, Meng Zhang, Qian Wang.

Authors and Affiliations

  1. State Key Laboratory of Organ Failure Research, Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Province Key Laboratory of Psychiatric Disorders, Collaborative Innovation Center for Brain Science, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China

    Ji-Hong Liu, Meng Zhang, Qian Wang, Ding-Yu Wu, Wei Jie, Neng-Yuan Hu, Jia-Zhuo Lan, Kai Zeng, Shu-Ji Li, Xiao-Wen Li, Jian-Ming Yang & Tian-Ming Gao

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Contributions

TG and JLiu designed the study. JLiu, QW, and JLan performed the behavior tests and analysis. JLiu and MZ performed the electrophysiology recordings. QW conducted the ELISA measurements. NH performed the immunofluorescence. WJ performed the Ca2+ imaging. DW conducted the stereotaxic microinjection. SL, KZ, and XL performed the western blotting. TG conceived the project and wrote the manuscript with the assistance of JLiu and JY.

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Correspondence to Tian-Ming Gao.

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Liu, JH., Zhang, M., Wang, Q. et al. Distinct roles of astroglia and neurons in synaptic plasticity and memory. Mol Psychiatry 27, 873–885 (2022). https://doi.org/10.1038/s41380-021-01332-6

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