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

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.

CCL2-mediated inflammatory pathogenesis underlies high myopia-related anxiety

“…The disruption of the immune barriers further aggravates local inflammation, leading to a vicious circle. Interestingly, the highly myopic mice showed increased monocyte infiltration, BBB disruption, and altered dendritic spine density in BLA and ventral hippocampus, which are closely related to anxiety 50 – 52 , implying a potential relationship among inflammation, BBB disruption and high myopia-related anxiety. The cytokines secreted by infiltrated leukocytes can cause BBB breakdown 53 – 55 , which has been seen in anxiety-related diseases such as chronic stress, neuropsychiatric lupus, and bipolar disorder 15 , 56 , 57 .…”