Involvement of a BH3-only apoptosis sensitizer gene Blm-s in hippocampus-mediated mood control

Pei Hsin Huang*, Tsung Ying Yang, Chia Wei Yeh, Sheng Min Huang, Ho Ching Chang, Yun Fen Hung, Wen Chia Chu, Kuan Hung Cho, Tzu Pin Lu, Po Hsiu Kuo, Li Jen Lee, Li Wei Kuo, Cheng Chang Lien, Hwai Jong Cheng

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Mood disorders are an important public health issue and recent advances in genomic studies have indicated that molecules involved in neurodevelopment are causally related to mood disorders. BLM-s (BCL-2-like molecule, small transcript isoform), a BH3-only proapoptotic BCL-2 family member, mediates apoptosis of postmitotic immature neurons during embryonic cortical development, but its role in the adult brain is unknown. To better understand the physiological role of Blm-s gene in vivo, we generated a Blm-s-knockout (Blm-s−/−) mouse. The Blm-s−/− mice breed normally and exhibit grossly normal development. However, global depletion of Blm-s is highly associated with depression- and anxiety-related behaviors in adult mutant mice with intact learning and memory capacity. Functional magnetic resonance imaging of adult Blm-s−/− mice reveals reduced connectivity mainly in the ventral dentate gyrus (vDG) of the hippocampus with no alteration in the dorsal DG connectivity and in total hippocampal volume. At the cellular level, BLM-s is expressed in DG granule cells (GCs), and Blm-s−/− mice show reduced dendritic complexity and decreased spine density in mature GCs. Electrophysiology study uncovers that mature vGCs in adult Blm-s−/− DG are intrinsically more excitable. Interestingly, certain genetic variants of the human Blm homologue gene (VPS50) are significantly associated with depression traits from publicly resourced UK Biobank data. Taken together, BLM-s is required for the hippocampal mood control function. Loss of BLM-s causes abnormality in the electrophysiology and morphology of GCs and a disrupted vDG neural network, which could underlie Blm-s-null-associated anxiety and depression.

Original languageEnglish
Article number411
JournalTranslational Psychiatry
Volume12
Issue number1
DOIs
StatePublished - Dec 2022

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