ProBDNF Signaling Regulates Depression-Like Behaviors in Rodents under Chronic Stress.
Chronic exposure to stressful environment is a key risk factor contributing to the development of depression. However, the mechanisms involved in this process are still unclear. Brain-derived neurotropic factor (BDNF) has long been investigated for its positive role in regulation of mood, although the role of its precursor, proBDNF, in regulation of mood is not known. In this study, using an unpredictable chronic mild stress (UCMS) paradigm we found that the protein levels of proBDNF were increased in the neocortex and hippocampus of stressed mice and this UCMS-induced upregulation of proBDNF was abolished by chronic administration of fluoxetine. We then established a rat model of UCMS and found that the expression of proBDNF/p75NTR/sortilin was upregulated, whereas the expression of mature BDNF and TrkB was downregulated in both neocortex and hippocampus of chronically stressed rats. Finally, we found that the injection of anti-proBDNF antibody via intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) approaches into the UCMS rats significantly reversed the stress-induced depression-like behavior and restored the exploratory activity and spine growth. Although intramuscular injection of AAV-proBDNF did not exacerbate the UCMS-elicited rat mood-related behavioral or pathological abnormalities, i.c.v. injection of AAV-proBDNF increased the depression-like behavior in naive rats. Our findings suggest that proBDNF plays a role in the development of chronic stress-induced mood disturbances in rodents. Central (i.c.v.) or peripheral (i.p.) inhibition of proBDNF by injecting specific anti-proBDNF antibodies may provide a novel therapeutic approach for the treatment of stress-related mood disorders.
Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.|Institute of Neuroscience, Molecular Clinic Institute, Kunming Medical University, Kunming, China.
Yin-Yin
YY
Bai
Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.|School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.
Chun-Sheng
CS
Ruan
Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
Chun-Rui
CR
Yang
School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.
Jia-Yi
JY
Li
Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
Zhi-Long
ZL
Kang
Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
Li
L
Zhou
Discipline of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
Dennis
D
Liu
Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.
Yue-Qing
YQ
Zeng
Institute of Neuroscience, Molecular Clinic Institute, Kunming Medical University, Kunming, China.
Ting-Hua
TH
Wang
Biomedical Engineering Research Center, Kunming Medical University, Kunming, China.
Chang-Fu
CF
Tian
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
Hong
H
Liao
School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.
Larisa
L
Bobrovskaya
Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, China.|School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.
Xin-Fu
XF
Zhou
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002908:Chronic Disease; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D003866:Depressive Disorder / Q000188:drug therapy / Q000209:etiology*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology; D005518:Food Preferences / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011498:Protein Precursors / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000150:complications* / Q000473:pathology; D013550:Swimming / Q000523:psychology
D000906:Antibodies; D018687:Antidepressive Agents, Second-Generation; D019208:Brain-Derived Neurotrophic Factor; D011498:Protein Precursors; D005473:Fluoxetine