Mice with Sort1 deficiency display normal cognition but elevated anxiety-like behavior.
Exposure to stressful life events plays a central role in the development of mood disorders in vulnerable individuals. However, the mechanisms that link mood disorders to stress are poorly understood. Brain-derived neurotrophic factor (BDNF) has long been implicated in positive regulation of depression and anxiety, while its precursor (proBDNF) recently showed an opposing effect on such mental illnesses. P75(NTR) and sortilin are co-receptors of proBDNF, however, the role of these receptors in mood regulation is not established. Here, we aimed to investigate the role of sortilin in regulating mood-related behaviors and its role in the proBDNF-mediated mood abnormality in mice. We found that sortilin was up-regulated in neocortex (by 78.3%) and hippocampus (by 111%) of chronically stressed mice as assessed by western blot analysis. These changes were associated with decreased mobility in the open field test and increased depression-like behavior in the forced swimming test. We also found that sortilin deficiency in mice resulted in hyperlocomotion in the open field test and increased anxiety-like behavior in both the open field and elevated plus maze tests. No depression-like behavior in the forced swimming test and no deficit in spatial cognition in the Morris water maze test were found in the Sort1-deficient mice. Moreover, the intracellular and extracellular levels of mature BDNF and proBDNF were not changed when sortilin was absent in vivo and in vitro. Finally, we found that both WT and Sort1-deficient mice injected with proBDNF in lateral ventricle displayed increased depression-like behavior in the forced swimming test but not anxiety-like behaviors in the open field and elevated plus maze tests. The present study suggests that sortilin functions as a negative regulator of mood performance and can be a therapeutic target for the treatment of mental illness.
School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, SA 5000, Australia. Electronic address: chunsheng.ruan@mymail.unisa.edu.au.
Chun-Sheng
CS
Ruan
Department of Pathology, Second Hospital of Tianjin Medical University, Tianjin 300211, China.
Chun-Rui
CR
Yang
School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, SA 5000, Australia.
Jia-Yi
JY
Li
School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, SA 5000, Australia.
Hai-Yun
HY
Luo
School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, SA 5000, Australia.
Larisa
L
Bobrovskaya
School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, SA 5000, Australia. Electronic address: xin-fu.zhou@unisa.edu.au.
Xin-Fu
XF
Zhou
D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency* / Q000235:genetics; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000235:genetics*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003071:Cognition / Q000502:physiology*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D012737:Sex Factors; D013315:Stress, Psychological / Q000235:genetics / Q000503:physiopathology; D013550:Swimming / Q000523:psychology; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D000099183:Sortilin
Anxiety-like behavior; Cognition; Depression-like behavior; Hyperlocomotion; Sortilin; proBDNF