Nitric oxide‐soluble guanylyl cyclase pathway as a contributor to age‐related memory impairment in Drosophila

• Published in: Aging cell 2022-09, Vol.21 (9), p.e13691-n/a
• Main Authors: Tonoki, Ayako, Nagai, Saki, Yu, Zhihua, Yue, Tong, Lyu, Sizhe, Hou, Xue, Onuki, Kotomi, Yabana, Kaho, Takahashi, Hiroki, Itoh, Motoyuki
• Format: Article
• Language: English
• Subjects: Age; aging; Animals; Drosophila; Drosophila - metabolism; Gene expression; Genetic screening; Genomes; glia; Guanylate cyclase; Guanylate Cyclase - genetics; Guanylate Cyclase - metabolism; Insects; Kinases; Life span; memory; Neuronal-glial interactions; Neurons; Nitric oxide; Nitric Oxide - metabolism; Nitric-oxide synthase; Proteins; Receptors, Cytoplasmic and Nuclear - genetics; RNA-mediated interference; soluble guanylyl cyclase; Soluble Guanylyl Cyclase - genetics; Sucrose; Transcriptomes
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13691

Age‐related changes in the transcriptome lead to memory impairment. Several genes have been identified to cause age‐dependent memory impairment (AMI) by changes in their expression, but genetic screens to identify genes critical for AMI have not been performed. The fruit fly is a useful model for studying AMI due to its short lifespan and the availability of consistent techniques and environments to assess its memory ability. We generated a list of candidate genes that act as AMI regulators by performing a comprehensive analysis of RNAsequencing data from young and aged fly heads and genome‐wide RNAi screening data to identify memory‐regulating genes. A candidate screen using temporal and panneuronal RNAi expression was performed to identify genes critical for AMI. We identified the guanylyl cyclase β‐subunit at 100B (gycβ) gene, which encodes a subunit of soluble guanylyl cyclase (sGC), the only intracellular nitric oxide (NO) receptor in fruit flies, as a negative regulator of AMI. RNAi knockdown of gycβ in neurons and NO synthase (NOS) in glia or neurons enhanced the performance of intermediate‐term memory (ITM) without apparent effects on memory acquisition. We also showed that pharmacological inhibition of sGC and NOS enhanced ITM in aged individuals, suggesting the possibility that age‐related enhancement of the NO‐sGC pathway causes memory impairment. Intermediate‐term memory (ITM) is negatively regulated by nitric oxide (NO) synthesis in glia and expression of soluble guanylyl cyclase (sGC) in neurons. Age‐dependent impairment of ITM can be reversed by inhibition of NOS and sGC, suggesting that overproduction of NO in glia and activation of sGC signaling in neurons causes age‐related memory impairment.