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The Fragile X Mental Retardation Protein (FMRP) is a canonical RNA-binding protein whose absence in humans leads to the development of the Fragile X Syndrome characterized by multiple phenotypes including neurodevelopmental disorders, intellectual disability, autism, and macroorchidism. The primary transcripts of the FMR1 gene undergo extensive alternative splicing processes, and multiple protein isoforms are produced. The predominantly cytoplasmic isoforms are translational regulators, while the roles of the nuclear ones have been neglected. In this study, we discovered that nuclear FMRP isoforms specifically associate with DNA bridges, aberrant genomic structures that form during mitosis and whose accumulation can drive genome instability by inducing DNA damage. Further localisation studies showed that a subset of FMRP-positive bridges contain proteins that have been shown to associate with specific DNA bridges known as ultrafine DNA bridges (UFBs), and surprisingly are RNA positive. Significantly, the depletion of nuclear FMRP isoforms promotes the accumulation of DNA bridges, correlating with the accumulation of DNA damages and cell death, unveiling an important function of these neglected isoforms.

Blood-brain barrier (BBB) alterations contribute to stress vulnerability and development of depressive behaviors. In contrast, neurovascular adaptations underlying stress resilience remain unexplored. Here, we report that high expression of astrocytic cannabinoid receptor 1 (CB1) in the nucleus accumbens (NAc) shell, particularly in the endfeet ensheathing blood vessels, is associated with resilience despite chronic social stress exposure. Viral-mediated overexpression of Cnr1 in astrocytes of the NAc shell has baseline anxiolytic effects and dampened stress-induced anxiety- and depression-like behaviors. It also reduced astrocyte inflammatory response and morphological changes following an immune challenge with the cytokine interleukin-6, linked to stress susceptibility and mood disorders. At the preventive and therapeutic level, physical exercise and antidepressant treatment increased perivascular astrocytic Cnr1 in mice. Loss of CNR1 was confirmed in the NAc astrocytes of depressed individuals. These findings suggest a role for the astrocytic endocannabinoid system in stress responses and possibly, human depression, via BBB modulation.