Lack of bombesin receptor-activated protein homologous protein impairs hippocampal synaptic plasticity and promotes chronic unpredictable mild stress induced behavioral changes in mice

Abstract

Bombesin receptor-activated protein (BRAP) and its homologous protein in mice, which is encoded by bc004004 gene, were expressed abundantly in brain tissues with unknown functions. We treated bc004004^-/- mice with chronic unpredictable mild stress (CUMS) to test whether those mice were more vulnerable to stress-related disorders. The results of forced swimming test, sucrose preference test, and open field test showed that after being treated with CUMS for 28 days or 35 days both bc004004^-/- and bc004004^+/+ mice exhibited behavioural changes and there was no significant difference between bc004004^+/+ and bc004004^-/-. However, behavioural changes were observed only in bc004004^-/- mice after being exposed to CUMS for 21 days, but not in bc004004^+/+ after 21-day CUMS exposure, indicating that lack of BRAP homologous protein may cause vulnerability to stress-related disorders in mice. In addition, bc004004^-/- mice showed a reduction in recognition memory as revealed by novel object recognition test. Since memory changes and stress related behavioural changes are all closely related to the hippocampus function we further analyzed the changes of dendrites and synapses of hippocampal neurons as well as expression levels of some proteins closely related to synaptic function. bc004004^-/- mice exhibited decreased dendritic lengths and increased amount of immature spines, as well as altered expression pattern of synaptic related proteins including GluN2A, synaptophysin and BDNF in the hippocampus. Those findings suggest that BRAP homologous protein may have a protective effect on the behavioural response to stress via regulating dendritic spine formation and synaptic plasticity in the hippocampus.

Keywords:

• BRAP
• stress
• CUMS
• synaptic plasticity
• dendritic spines
• hippocampus

Author contributions

X. Yao performed and analyzed most of the experiments; H. Wang, J. Zheng, J. Wang and Z. Peng performed immunostaining of BRAP in brain tissues, and the co-immunoprecipitation; X. Yao, H.Wang, J. Zheng, R. Liu, W. Zhang, J.Zeng, S. Zuo and H. Chen maintained the animals; X. Qu designed the research and wrote the manuscript; X. Qin and H. C. Weber reviewed and commented on the manuscript; H. C. Weber corrected the language.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was primarily supported by Natural Science Foundation of Hunan Province Grant 2020JJ4688 and National Natural Science Foundation of China (NSFC) Grant 81570026 (to Xiangping Qu), NSFC Grant 81970033 (to Xiaoqun Qin). It was also supported by the following grants: Natural Science Foundation of Hunan Province Grant 2020JJ4776 (to Yang Xiang), NSFC Grant 82070034, Natural Science Foundation of Hunan Province Grant 2021JJ30898 and Open Foundation of Hunan College Innovation Program Grant 20K142 (to Chi Liu), NSFC Grant 31900424 and Natural Science Foundation of Hunan Province Grant 2019JJ50760 (to Lang Pan), and the Open Sharing Fund for the Lager-scale Instruments and Equipment of Central South University.