Ca2+ -dependent activator protein for secretion 1 promotes spontaneous recovery in ischemic stroke by regulating BDNF secretion.

ABSTRACT

Ischemic stroke triggers a cascade of events that facilitates neural protection and spontaneous recovery, which accounts for a major part of functional recovery. Despite the cellular and molecular facilitations on neural protection, the molecular mechanisms of spontaneous recovery have not been fully understood. Ca2+ -dependent activator protein for secretion 1 (CAPS1), a member of CAPS family, plays a major role in synaptic transmission and synaptic effectiveness by regulating vesicle exocytosis. Here, the molecular mechanism of CAPS1 in spontaneous recovery after ischemic stroke was studied. In this study, transient left middle cerebral artery occlusion (MCAO) was used as the ischemic stroke model. The whole brain magnetic resonance imaging (MRI) and neurological score analysis showed decreased infarct volume and neurological scores at 7 days as compared with 1 day after MCAO, suggesting the spontaneous recovery. Elisa and Western blot analysis showed elevated BDNF and CAPS1 expression levels in bilateral hippocampus at both 1 day and 3 days after MCAO. Then, inhibition of CAPS1 by adeno-associated virus (AAV) microinjection in the hippocampus attenuated the spontaneous recovery of both motor and memory impairment induced by MCAO. In addition, elevated p-TrkB levels were detected after MCAO, which were reduced by CAPS1-AAV microinjection, indicating that CAPS1 could induce BDNF secretion after ischemic stroke. Moreover, we found elevated combination of CAPS1 with dense core vesicles (DCV) in the hippocampus at both 1 day and 3 days after MCAO, which could also be inhibited by CAPS1-AAV microinjection, indicating the potential mechanism of CAPS1 in regulating BDNF release after MCAO. Finally, we found that CAPS1/BDNF signaling could influence the neurogenesis in the hippocampus after MCAO. In conclusion, CAPS1 regulates neurogenesis by up-regulating BDNF release in the hippocampus, which finally facilitate spontaneous recovery after ischemic stroke.