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BACE1 in PV interneuron tunes hippocampal CA1 local circuits and resets priming of fear memory extinction

Molecular Psychiatry volume 28, pages 4151–4162 (2023)Cite this article

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Abstract

BACE1 is the rate-limiting enzyme for β-amyloid (Aβ) production and therefore is considered a prime drug target for treating Alzheimer’s disease (AD). Nevertheless, the BACE1 inhibitors failed in clinical trials, even exhibiting cognitive worsening, implying that BACE1 may function in regulating cognition-relevant neural circuits. Here, we found that parvalbumin-positive inhibitory interneurons (PV INs) in hippocampal CA1 express BACE1 at a high level. We designed and developed a mouse strain with conditional knockout of BACE1 in PV neurons. The CA1 fast-spiking PV INs with BACE1 deletion exhibited an enhanced response of postsynaptic N-methyl-D-aspartate (NMDA) receptors to local stimulation on CA1 oriens, with average intrinsic electrical properties and fidelity in synaptic integration. Intriguingly, the BACE1 deletion reorganized the CA1 recurrent inhibitory motif assembled by the heterogeneous pyramidal neurons (PNs) and the adjacent fast-spiking PV INs from the superficial to the deep layer. Moreover, the conditional BACE1 deletion impaired the AMPARs-mediated excitatory transmission of deep CA1 PNs. Further rescue experiments confirmed that these phenotypes require the enzymatic activity of BACE1. Above all, the BACE1 deletion resets the priming of the fear memory extinction. Our findings suggest a neuron-specific working model of BACE1 in regulating learning and memory circuits. The study may provide a potential path of targeting BACE1 and NMDAR together to circumvent cognitive worsening due to a single application of BACE1 inhibitor in AD patients.

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Fig. 1: BACE1 deletion did not change the electrophysiological properties of CA1 PV INs.
Fig. 2: The CA1 PV INs with BACE1 deletion received a normal AMPAR-, but an enhanced NMDAR-mediated excitatory transmission.
Fig. 3: BACE1 deletion made MK-801 a greater degree of blockade with NMDARs but left intact the reliability in synaptic integration of CA1 PV INs.
Fig. 4: BACE1 deletion in PV INs reorganized the inhibitory/excitatory synaptic transmission on CA1 PNs in a non-uniform pattern.
Fig. 5: Specific local recovery of BACE1 expression rescued the NMDAR EPSC in PV INs and AMPAR EPSC in CA1 deep layer PNs in an enzymatic-dependent manner.
Fig. 6: BACE1 deletion in CA1 PV INs reset the priming of fear memory extinction.

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Data availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We thank Hua Li and Hua Wei from Capital Medical University, China for their technical support. This work was supported by the National Natural Science Foundation of China (81771145, 81971004, 81571038 to YZ), Beijing Natural Science Foundation (5202006 to YZ).

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  1. These authors contributed equally: Xuansheng Xiao, Xiaotong Wang, Ke Zhu, Lijuan Li.

Authors and Affiliations

  1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China

    Xuansheng Xiao, Xiaotong Wang, Ke Zhu, Lijuan Li, Ying He, Jinglan Zhang, Hanning Hu, Yanqiu Cui & Yan Zheng

  2. Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, China

    Xuansheng Xiao, Xiaotong Wang, Ke Zhu, Lijuan Li, Ying He, Linying Li, Hanning Hu, Jianliang Zhang & Yan Zheng

  3. Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China

    Linying Li & Jianliang Zhang

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Contributions

Virus-injection, tests of behavior and chemogenetics were performed by XX; physiological data were provided by XW, KZ and YZ; LL performed immunostaining and reconstruction of dendritic spine; XX and other co-authors performed quality control and statistical analysis in double-blind for data. YZ designed the study and wrote the manuscript with all other authors’ help.

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Correspondence to Yan Zheng.

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Xiao, X., Wang, X., Zhu, K. et al. BACE1 in PV interneuron tunes hippocampal CA1 local circuits and resets priming of fear memory extinction. Mol Psychiatry 28, 4151–4162 (2023). https://doi.org/10.1038/s41380-023-02176-y

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