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Regulation of habenular G-protein gamma 8 on learning and memory via modulation of the central acetylcholine system

Abstract

Guanine nucleotide binding protein (G protein) gamma 8 (Gng8) is a subunit of G proteins and expressed in the medial habenula (MHb) and interpeduncular nucleus (IPN). Recent studies have demonstrated that Gng8 is involved in brain development; however, the roles of Gng8 on cognitive function have not yet been addressed. In the present study, we investigated the expression of Gng8 in the brain and found that Gng8 was predominantly expressed in the MHb–IPN circuit of the mouse brain. We generated Gng8 knockout (KO) mice by CRISPR/Cas9 system in order to assess the role of Gng8 on cognitive function. Gng8 KO mice exhibited deficiency in learning and memory in passive avoidance and Morris water maze tests. In addition, Gng8 KO mice significantly reduced long-term potentiation (LTP) in the hippocampus compared to that of wild-type (WT) mice. Furthermore, we observed that levels of acetylcholine (ACh) and choline acetyltransferase (ChAT) in the MHb and IPN of Gng8 KO mice were significantly decreased, compared to WT mice. The administration of nAChR α4β2 agonist A85380 rescued memory impairment in the Gng8 KO mice, suggesting that Gng8 regulates cognitive function via modulation of cholinergic activity. Taken together, Gng8 is a potential therapeutic target for memory-related diseases and/or neurodevelopmental diseases.

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Fig. 1: Habenula-specific expression of Gng8 and generation of Gng8 KO mice.
Fig. 2: Identification of Gng8-expressing cell types in the MHb and IPN.
Fig. 3: Impaired cognitive behaviors and reduction of cholinergic activity in Gng8 KO mice.
Fig. 4: HFS-induced LTP was attenuated in Gng8 KO mice.
Fig. 5: nAChR α4β2 agonist A85380 recused memory deficit in Gng8 KO mice.

Data availability

All data generated and analyzed during this study are included in this article.

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Acknowledgements

We would like to thank Dr Hyosang Lee for critical comments on the manuscript.

Funding

This work was supported by grants from the National Research Foundation of the Korean government (NRF-2016M3C7A1905384, 2018M3A9B8021980) and Kyung Hee University in 2019 (KHU-20191211).

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IS and C-HK conceived the study and participated in the design of the study and writing of the manuscript. H-JL, T-IC, Y-MK, SL, ISB, SAM, BH, D-YY, KSS, YKK, CM, JHR, and H-SH performed experiments, statistical analyses, and writing of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Cheol-Hee Kim or Insop Shim.

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Lee, Hj., Choi, TI., Kim, YM. et al. Regulation of habenular G-protein gamma 8 on learning and memory via modulation of the central acetylcholine system. Mol Psychiatry 26, 3737–3750 (2021). https://doi.org/10.1038/s41380-020-00893-2

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