Postnatal downregulation of Fmr1 in microglia promotes microglial reactivity and causes behavioural alterations in female mice

Molecular Autism, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 7, 2025

Fragile X syndrome is caused by the loss of Fmr1 gene expression. Deletion in various neuronal and non-neuronal subpopulations brain mice leads to cell-type-specific effects. Microglia, immune cells critical for refinement circuits during development, have been implicated neurodevelopmental disorders, including fragile syndrome. However, it unknown whether reduced expression microglia molecular behavioral phenotypes. We downregulated early late postnatal development studied effect on microglial morphology distinct behaviours. Female, but not male, adult with downregulation exhibited reactive phenotypes, enhanced self-grooming alterations social interaction. Downregulation induced a milder phenotype, characterized impaired preference novelty without affecting morphology. The its encoded protein FMRP contributes behavioural phenotypes sex-specific manner.

Language: Английский

Glial Cells in Spinal Muscular Atrophy: Speculations on Non-Cell-Autonomous Mechanisms and Therapeutic Implications

Neurology International, Journal Year: 2025, Volume and Issue: 17(3), P. 41 - 41

Published: March 13, 2025

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous deletions or mutations in the SMN1 gene, leading to progressive motor neuron degeneration. While SMA has been classically viewed as neuron-autonomous disease, increasing evidence indicates significant role of glial cells—astrocytes, microglia, oligodendrocytes, and Schwann cells—in disease pathophysiology. Astrocytic dysfunction contributes vulnerability through impaired calcium homeostasis, disrupted synaptic integrity, neurotrophic factor deficits. Microglia, reactive gliosis complement-mediated stripping, exacerbate neurodegeneration neuroinflammation. Oligodendrocytes exhibit differentiation metabolic support, while cells display abnormalities myelination, extracellular matrix composition, junction maintenance, further compromising function. Dysregulation pathways such NF-κB, Notch, JAK/STAT, alongside upregulation complement proteins microRNAs, reinforces non-cell-autonomous nature SMA. Despite advances SMN-restorative therapies, they do not fully mitigate dysfunction. Targeting pathology, including modulation astrogliosis, microglial polarization, myelination deficits, represents critical avenue for therapeutic intervention. This review comprehensively examines multifaceted roles highlights emerging glia-targeted strategies enhance treatment efficacy improve patient outcomes.

Language: Английский