Neuronal apoptosis and synaptic density in the dentate gyrus of ischemic rats' response to chronic mild stress and the effects of Notch signaling.
Our previous research highlighted an inconsistency with Notch1 signaling-related compensatory neurogenesis after chronic mild stress (CMS) in rodents suffering from cerebral ischemia, which continue to display post-stroke depressive symptoms. Here, we hypothesize that CMS aggrandized ischemia-related apoptosis injury and worsened synaptic integrity via gamma secretase-meditated Notch1 signaling. Adult rats were exposed to a CMS paradigm after left middle cerebral artery occlusion (MCAO). Open-field and sucrose consumption testing were employed to assess depression-like behavior. Gene expression of pro-apoptotic Bax, anti-apoptotic Bcl-2, and synaptic density-related synaptophysin were measured by western blotting and real-time PCR on Day 28 after MCAO surgery. CMS induced depressive behaviors in ischemic rats, which was accompanied by an elevation in Bax/bcl-2 ratio, TUNEL staining in neurons and reduced synaptophysin expression in the dentate gyrus. These collective effects were reversed by the gamma-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenyl-glycine t-butyl ester). We found that post-stroke stressors made neurons in the dentate gyrus vulnerable to apoptosis, which supports a putative role for Notch signaling in neural integrity, potentially in newborn cells' synaptic deficit with regard to preexisting cells. These findings suggest that post-stroke depression therapeutically benefits from blocking gamma secretase mediated Notch signaling, and whether this signaling pathway could be a therapeutic target needs to be further investigated.
Department of Endocrinology, affiliated ZhongDa Hospital of Southeast University, Nanjing, People's Republic of China.
Shaohua
S
Wang
Yang
Y
Yuan
Wenqing
W
Xia
Fengfei
F
Li
Yan
Y
Huang
Yi
Y
Zhou
Yijing
Y
Guo
D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology*; D003863:Depression / Q000150:complications; D008297:Male; D009474:Neurons / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013315:Stress, Psychological / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020521:Stroke / Q000523:psychology; D013569:Synapses / Q000473:pathology*; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D051880:Receptors, Notch; D051028:bcl-2-Associated X Protein