Mifepristone repairs region-dependent alteration of synapsin I in hippocampus in rat model of depression.
Clinical investigations present much evidence that the glucocorticoid receptor (GR) antagonist mifepristone leads to a rapid amelioration of depression. The molecular mechanisms of mifepristone involved in the treatment of depression are not fully understood. Depression is associated with hippocampal plasticity, for which increased excitatory amino acid (EAA) release in CA3 induced by chronic stress is responsible, and glucocorticoids have a permissive role and act synergistically with EAAs in producing neuronal damage. Moreover, glucocorticoids increase synapsin I, which has a key role in the release of neurotransmitter, including EAAs. Hereby, we hypothesize that major depression involves synapsin I alteration and that mifepristone blocks this alteration. In the present study, we observed both the expression of hippocampal synapsin I and depression-associated behavior in a rat model of depression induced by chronic unpredictable mild stress (CUMS). The result showed that a region-dependent synapsin I alteration occurs in the rat hippocampus after 21 days of CUMS, that is, it increases in dentate gyrus (DG)/CA3 and decreases in the CA1 region. Correlation analysis indicated that the decrease of synapsin I in CA1 is highly correlated with the increase in the DG/CA3 subfield. Simultaneously, the region-dependent alteration of synapsin I is correlated with depression-associated behaviors. Both the alteration of synapsin I and the depression-associated behavior were rapidly restored after treatment with mifepristone for 1 week. The result suggests that the molecular mechanism underlying the treatment of depression with mifepristone is associated with the rapid repair of the synaptic alteration.
Wu
Li-Min
LM
Hefei National Laboratory for Physical Sciences at Microscale and Department of Neurobiology and Biophysics, School of Life Science, University of Science and Technology of China, Hefei, China.
Han
Hui
H
Wang
Qu-Nan
QN
Hou
Hai-Long
HL
Tong
Hui
H
Yan
Xue-Bo
XB
Zhou
Jiang-Ning
JN
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy / Q000473:pathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005518:Food Preferences / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects*; D006727:Hormone Antagonists / Q000627:therapeutic use*; D008297:Male; D015735:Mifepristone / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013223:Statistics as Topic; D016704:Synapsins / Q000235:genetics / Q000378:metabolism*
D006727:Hormone Antagonists; D016704:Synapsins; D015735:Mifepristone