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    • The present study chose the fdh

    2021-09-08

    The present study chose the fdh gene, the homolog of mammalian GSNOR, to generate UAS-fdh and fdh double-stranded RNA interference (ds-RNAi) transgenic Drosophila. These transgenic models were used to study the effect of GSNOR activity modulation on visual learning and memory and to explore the possible mechanisms of learning and memory mediated by NO metabolism.
    Experimental procedures
    Results
    Discussion The present study investigated the relationship between NO metabolism and visual pattern memory in D. melanogaster. Results demonstrated that over-expression of fdh in adulthood resulted in memory defect in a visual learning paradigm and fdh participated in visual pattern memory in specific neurons. PKG over expression could rescue the memory defect caused by over-expression of fdh. Furthermore, flies with downregulated bioactivity of NOS displayed the same visual pattern memory defects as fdh over-expression flies (Fig. S1). Meanwhile, there were multiple proteins denitrosated in the memory-deficient flies. No specific phenotype was detected in the fdh down-regulated flies, which could be due to the compensatory effect of other Tranilast Sodium synthesis that exhibit GSNO reductase activity [40], [41]. Based on results from the present study and previously reported data [42], we proposed a model for the role of NO in visual pattern memory in Drosophila: the homeostasis of NO is doubly-controlled by NOS/GSNOR; GSNOR controls NO metabolism via GSNO regulation and NOS controls NO synthesis by using arginine as a substrate. Modulation of either GSNOR or NOS can regulate NO bioactivity. Over-expression of fdh resulted in NO imbalance, thereby affecting the NO-cGMP-PKG pathway and protein S-nitrosation and, ultimately, learning and memory function (Fig. 5). Our results demonstrated that NO metabolism regulated by fdh is crucial in visual pattern memory. In this study, both the NO-cGMP-PKG pathway and protein S-nitrosation may be involved in fdh-regulated learning and memory. PKG deficiency has been shown to result in learning and memory defects [24], and GSNOR inhibitors increase the soluble guanylyl cyclase (sGC) activity and enhance signal transduction of the NO-cGMP pathway [39]. Therefore, over-expression of the fdh gene in the present model may block sGC activity. In turn, it could lead to decreased PKG activity via the NO-cGMP-PKG pathway, resulting in visual pattern memory defect. Moreover, because NO bioactivity was exerted through cGMP-dependent and cGMP-independent pathways, protein S-nitrosation may also play a role in learning and memory. It has been reported that S-nitrosation of the N-ethylmaleimide-sensitive factor (NSF) induces cerebellar LTP by modulating surface expression of AMPA receptors [43] and S-nitrosation of cyclic nucleotide-gated (CNG) channels, which could affect learning and memory by affecting olfactory and visual transduction [44]. In the present study, multiple vesicle-mediated transport proteins were denitrosated, such as Arr1, Syt1, and Rop. Syt1 is functionally related to neurotransmitter secretion and synaptic vesicle endocytosis, which are important in learning and memory mechanisms. These results suggested that protein S-nitrosation/denitrosation modification could contribute to memory defect in fdh over-expressing flies. Results from the GO analysis revealed that some denitrosated proteins in fdh over-expressing flies were related to the process of visual perception, which could interfere with visual learning and memory. Therefore, Fourier analysis was used to evaluate the ability of flies to discriminate between patterns [24]. As shown in Supplementary Fig. S2A, visual discrimination was not significantly different between fdh over-expressing flies, fdh dsRNAi flies, and the genetic control flies. A defect in thermo-tolerance can induce low memory performance in fdh over-expressing flies. Therefore, the present study measured dwelling time of the transgenic flies during the first and last training [45]. As shown in Fig. S2B, there was no significant change in thermo-tolerance. These results excluded the effects of thermo-tolerance and pattern discrimination on visual pattern memory in fdh over-expressing flies.