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NSUN5 Deficiency Drives Anxiety-Like Behaviors in Mice via Increased Microglial Activation and Impaired LTD Induction in the Basolateral Amygdala
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DOI：10.1096/fj.202600754R.png)
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Abstract
En 中文
Williams-Beuren Syndrome (WBS), is a neurodevelopmental disorder characterized by anxiety, hypersociality and neurocognitive abnormalities, resulting from a heterozygous microdeletion on chromosome 7q11.23. A cytosine-5 RNA methyltransferase, NSUN5, is one of the deleted genes, which has been linked to cognitive deficits in WBS patients. However, the relation of NSUN5 to anxiety disorders and underlying mechanisms remain unknown. Here, we report that NSUN5 deficiency triggers anxiety-like behaviors without hypersociality in both adult male and female mice. NSUN5 exhibits specific expression in oligodendrocyte precursor cells (OPCs) within the basolateral amygdala (BLA), which is one of the main brain regions linked to anxiety. In addition, NSUN5 deficiency in mice leads to reduced OPCs proliferation accompanied with microglial activation. Mechanistically, we revealed that the specific decline in secretion of OPCs-derived fibroblast growth factor 2 (FGF2) resulted in microglial activation and exacerbated the levels of TNF alpha and IL-1 beta cytokines in NSUN5-deficient mice. Field excitatory postsynaptic potentials (fEPSPs) slopes at external capsule BLA synapse were increased in NSUN5-deficient mice. Moreover, an increase in paired-pulse inhibition and an impairment of long-term depression (LTD) induction were observed in NSUN5-deficient mice, which could be rescued either by intra-BLA injection of recombinant mouse FGF2 (rmFGF2) or by pharmacological suppression of microglial activation with minocycline. Furthermore, the anxiety-like behaviors in NSUN5-deficient mice were also relieved by rmFGF2 or minocycline treatments. Taken together, our study unveils a previously unknown effect of NSUN5 on anxiety disorders and a role of NSUN5 in regulating OPCs-microglia interaction and synaptic plasticity of BLA.
Keywords:
anxiety
basolateral amygdala
NSUN5
oligodendrocyte precursor cells
synaptic plasticity
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