Increased Microglial Activity, Impaired Adult Hippocampal Neurogenesis, and Depressive-like Behavior in Microglial VPS35-Depleted Mice

• DOI: 10.1523/jneurosci.3621-17.2018
• Publication Date: 2018-05-31T15:36:18Z
• Authors: Joanna Ruth Appel; Shiyang Ye; Fulei Tang; Dong Sun; Hongsheng Zhang; Lin Mei; Wen-Cheng Xiong
• Keywords: Male; Mice, Knockout; Neurons; 0303 health sciences; Depression; Neurogenesis; Vesicular Transport Proteins; Cell Differentiation; Hippocampus; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Animals; Microglia

Vacuolar sorting protein 35 (VPS35) is a critical component of retromer, which essential for selective endosome-to-Golgi retrieval membrane proteins. VPS35 deficiency implicated in neurodegenerative disease pathology, including Alzheimer9s (AD). However, exactly how loss promotes AD pathogenesis remains largely unclear. expressed various types cells the brain, neurons and microglia. Whereas neuronal plays role preventing neurodegeneration, microglial unknown. Here we provide evidence VPS359s function activation promoting adult hippocampal neurogenesis. microglia regions mouse with unique distribution pattern brain region-dependent manner. Conditional knocking out male mice results regionally increased density activity subgranular zone dentate gyrus (DG), accompanied by elevated neural progenitor proliferation, but decreased differentiation. Additionally, newborn mutant DG show impaired dendritic morphology reduced spine density. When examining behavioral phenotypes these animals, VPS3S-depleted display depression-like behavior impairment long-term recognition memory. At cellular level, VPS35-depleted have grossly enlarged vacuolar structures phagocytic toward postsynaptic marker PSD95, may underlie spines observed DG. Together, findings identify an important suppressing neurogenesis, are both processes involved pathogenesis. <b>SIGNIFICANCE STATEMENT</b> The presented here first <i>in vivo</i> that (VPS35)/retromer regulating when retromer mechanics disrupted, surrounding tissue can be affected These present novel, microglial-specific raise multiple questions regarding mechanisms underlying our observations. also myriad implications field research dysfunction pathophysiology. Furthermore, they implicate pivotal regulation neurogenesis survival/integration hippocampus.