Fmr1 Deletion and Early-Life Stress Interact to Increase Cell Proliferation and Glial Populations at the Expense of Immature Neurons in the Adult Dentate Gyrus

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Abstract
Fragile X Syndrome (FXS) is an inherited cause of intellectual disability and autism, arising from silencing of the Fmr1 gene and loss of Fragile X Messenger Ribonucleoprotein 1 (FMRP). FMRP is an RNA-binding protein critically involved in neurodevelopmental processes, including neurogenesis. We examined the proliferation and maturation of adult-born dentate granule cells (abDGCs) and glial populations in Fmr1 knockout (KO) and wild-type (WT) mice at 4, 12, and 24 weeks of age under control and early-life stress (ELS) conditions. Based on prior findings, we hypothesized that KO mice would exhibit increased neurogenesis and atypical responses to ELS compared with WT mice. Using immunohistochemistry, we quantified multiple stages of neurogenesis in the dentate gyrus, including proliferating (Ki67+), immature (doublecortin [DCX]+), and apoptotic (cleaved caspase-3 [CC3]+) cells. We also assessed glia using Iba1 (microglia) and GFAP (astrocytes) immunoreactivity. KO mice displayed significantly increased Ki67+ proliferating and reduced CC3+ apoptotic cells across ages, accompanied by increased Iba1+ and GFAP+ glial densities. However, KO mice exhibited fewer DCX+ neuroblasts at later time points. When reared in ELS conditions, KO mice show blunted or no changes in neurogenesis and glial populations relative to WT mice reared in ELS conditions or KO mice in control conditions. These results indicate that FMRP loss disrupts hippocampal neurogenesis by increasing cell proliferation while limiting neuronal maturation and expanding glial populations. Moreover, the absence of neurogenic and glial responses to ELS in KO mice highlights a gene–environment interaction that may influence FXS-related neuropathology by limiting the adaptive capacity of the hippocampal neurogenic niche.
Funding Information
  • National Institute of Neurological Disorders and Stroke (R15NS088776)

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