Abstract
[Purpose]Fibronectin type III domain containing 5 (FNDC5)/irisin is an exercise-induced myokine, which contributes to cognitive functions. However, the relationship between the neuroprotective effects of FNDC5/irisin and hippocampal dendritic remodeling and astrocyte-secreted factors remains unclear. Therefore, we explored whether subchronic recombinant irisin treatment affected hippocampal morphology and some astrocyte-derived molecules.[Methods]Mice were intraperitoneally injected with irisin (0.5 μg/kg/day) for seven days, followed by their sacrifice two days later. Hippocampal morphometric parameters were analyzed and pgc-1a, fndc5, bdnf, and some astrocyte-derived factors mRNA levels were measured.[Results]Dendritic length, arborization, and spine density were enhanced by irisin regimen in hippocampal CA1 and CA3 areas. Hippocampal pgc-1a, fndc5, and bdnf mRNA levels were significantly increased by irisin treatment. Moreover, hevin mRNA levels were significantly enhanced, whereas tgf-b1 levels downregulated by irisin treatment.[Conclusion]FNDC5/irisin has dendritogenic activity probably through hevin induction and TGF-β1 suppression.
Highlights
Irisin, which is cleaved from fibronectin type III domain containing 5 (FNDC5), is an exercise-responded myokine under controlling peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)[1]
We found that total dendritic length (CA1: t8 = -2.38, p < 0.05; CA3: t8 = -2.59, p < 0.05; dentate gyrus (DG): t8 = 0.16, p > 0.05), branch point (CA1: t8 = -2.84, p < 0.05; CA3: t8 = -2.50, p < 0.05; DG: t8 = -0.40, p > 0.05), and spine density (CA1: t8 = -3.37, p < 0.05; CA3: t8 = -3.13, p < 0.05; DG: t8= -0.60, p > 0.05) were significantly enhanced by irisin treatment in hippocampal CA1 and CA3 areas, but not DG (Fig. 1B-D)
We found that the exogenous irisin treatment enhanced the hippocampal PGC-1α (t6 = -3.99, p < 0.01), FNDC5 (t6 = -5.13, p < 0.01), and brain-derived neurotrophic factor (BDNF) (t6 = -3.60, p < 0.05) mRNA levels (Fig. 1E)
Summary
Irisin, which is cleaved from fibronectin type III domain containing 5 (FNDC5), is an exercise-responded myokine under controlling peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α)[1]. Mounting evidence has described the synaptic plasticity-promoting role of irisin in memory processes under physiological and pathological conditions such as Alzheimer’s disease (AD)[2,3]. Astrocytes of the gray matter are structural and functional components of synapses, which secrete diverse synaptogenic signals to control synaptic formation and function, including thrombospondins (TSPs), hevin, secreted protein acidic and rich in cysteine (SPARC), and transforming growth factor β-1 (TGF-β1)[5,6,7,8]. The astrocyte-secreted factors have been well-studied in a purified retinal ganglion cell (RGC) culture system, in which TSPs and hevin induce the excitatory synapse formation by binding to α2δ-1 and bridging between Neurexin-1α and neuroligin-1B, respectively[5,9]. Hippocampal TGF-β1 overexpression or D-serine-mediated TGF-β1 signaling in cortex neurons promoted excitatory synaptogenesis, while TGF-β1 induced inhibitory synaptogenesis through CaM kinase II signaling[11,12,13]
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