Na+/K+-ATPase is a novel target to treat anxiety / 中国药理学与毒理学杂志

ABSTRACT

OBJECTIVE Na+/K+-ATPase(NKA)is a large membrane protein expressed universally in all cells.It is indispensable for the maintenance of ionic gradient.We previously reported that the dysfunction of this pump in neurons and astrocytes contributes to stroke and neurodegenerative diseases,respectively.However,its roles in the microglia and stress-related diseases are still unclear.METHODS Two classical models,chronic restraint stress(CRS)model and electronic foot shock(ES)model,were used to study the pathogenesis of anxi-ety in either NKAα1 global knockout(NKAα1 GKO)mice or NKA α1 conditional knockout(NKAα1 CKO)mice.Behavioral tests like open-field test,elevated plus maze,Morris water maze,novel object recognition test and gait imaging test were performed.A variety of molecular bio-logical methods were employed,including RNA sequenc-ing(RNA-seq)analyses,immunofluorescence and elec-trophysiological recordings etc.RESULTS NKAα1 defi-ciency had a broad impact on physical stress-induced anxiety-like behavior,but failed to exacerbate CRS induced memory deficits.Electrophysiology experiment showed that NKAα1 GKO and NKAα1 CKO mice exhibit-ed neuronal hyperexcitability under chronic stress.The underlying mechanisms may involve neuroinflammation,as NKAα1 deficiency exacerbated stress-induced microg-lia activation in vivo.Similarly,inhibition or downregula-tion of NKA α 1 aggravated LPS + ATP-induced inflam-mation in vitro.DR5-12D,a monoclonal antibody against the DR-region of NKAa1,improved stress-induced anxiety-like behavior through amelioration of the neuronal hyper-excitability and neurogenesis deficit in the ventral hippo-campus of mice.CONCLUSION NKA is closely related to neuroinflammation in microglia and DR-region of NKA a1 subunit may serve as a novel target to treat stress-induced anxiety.