Abstract
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.
Highlights
The pathophysiology of post-stroke depression (PSD) remains elusive because of its proposed multifactorial nature
Results from two-way ANOVA indicated that middle cerebral artery occlusion (MCAO)+chronic mild stress (CMS) significantly reduced the locomotor activity [F (4, 50) = 12.55, P,0.0001] and the frequency of rearing [F (4, 50) = 14.67, P,0.0001]
Bonferroni post hoc tests confirmed that the locomotor and rearing activities of the MCAO+CMS group animals were significantly lowered (P,0.001 in all cases; in comparison to the baseline value and the CON group level) on day 28 after ischemia
Summary
The pathophysiology of post-stroke depression (PSD) remains elusive because of its proposed multifactorial nature. Transient global [9] or focal ischemia [10,11] provokes the migration newly born neurons from the subgranular zone (SGZ) into the granule cell layer of the DG. They subsequently incorporate into the synaptic circuitry. Elevated neurogenesis in CMS-treated ischemic stroke animals is accompanied with depressive symptoms. This finding implies that neural integrity is vital for the replacement functions of newborn neurons during ischemic injury. In the hippocampus of ischemic animals experiencing CMS, gamma secretase–mediated Notch signaling is potentially involved in apoptosis and the impaired formation of newborn synapses
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