Abstract
TSPO, an 18 kDa translocator protein, has received increased attention due to its antidepressant-anxiolytic effects. The balance between glutamatergic and GABAergic (E: I) in the medial prefrontal cortex (mPFC) is crucial for antidepressant-anxiolytic effects. However, no evidence is available to clarify the relationship between TSPO and E:I balance. In the present study, we used the TSPO global-knockout (KO) and TSPO wild-type (WT) mice to assess the effects of TSPO on antidepressant-anxiolytic effects of YL-IPA08 (a novel TSPO ligand) and the underlying neurobiological mechanism. Additionally, a multichannel electrophysiological technique was used to explore the effects of YL-IPA08 on pyramidal neurons and interneurons in mPFC. Open field test (OFT) and elevated plus maze (EPM) test revealed that a single dose of YL-IPA08 (0.3 mg/kg, i.p.) exhibited significant anxiolytic actions in WT mice except in KO mice. In only WT mice, significant antidepressant effects were observed in tail suspension test (TST) and forced swim test (FST). The multichannel electrophysiological technique demonstrated that YL-IPA08 significantly increased the firing rates of pyramidal neurons and decreased those of interneurons. Further studies illustrated that the firing rates of glutamatergic might be antagonized by PK11195 (a classic TSPO antagonist). Our results suggest that YL-IPA08 might regulate the E:I balance in mPFC, mediated by TSPO. In summary, TSPO regulates E:I functional balance in mPFC, play a critical role in antidepressant-anxiolytic effects of YL-IPA08, and provide a potential target site for the development of antidepressant and anxiolytic drugs.
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Change history
10 October 2022
A Correction to this paper has been published: https://doi.org/10.1007/s11011-022-01065-7
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Funding
This research was supported by the Natural Science Foundation of China (No 81771129, 81773708, and 81173036) and the Military Medical Technology Incubation Project for Youth (20QNPY094).
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** Yuan: Investigation, Performed multiple tests, Data acquisition and analysis, Writing-Original Draft, Visualization; Jun-Qi Yao: Performed the TSTand FST tests, data acquisition and analysis; **n-**n Fang: Revised the manuscript; Wei Dai: Methodology; Supervised the experiments; Yun-Hui Wang: Revised the manuscript; Li-Ming Zhang: Conceptualization, Writing-review and editing; Yun-Feng Li: Resources, Conceptualization, Supervision, Project Administration; and all participants agreed to publish the studies data.
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Yuan, J., Yao, JQ., Fang, XX. et al. Involvement of regulation of the excitation:inhibition functional balance in the mPFC in the antidepressant-anxiolytic effect of YL-IPA08, a novel TSPO ligand. Metab Brain Dis 37, 2305–2314 (2022). https://doi.org/10.1007/s11011-022-00961-2
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DOI: https://doi.org/10.1007/s11011-022-00961-2