Abstract
In the hippocampus, delayed neuronal death is normally seen in neurons of the CA1 region but not in those of the CA3 region. Astrocytes have been reported to play multiple supporting or pathological roles in neuronal functioning. While evidence indicates that astrocytes could exert neuroprotective effects following ischemia, the possible underlying mechanisms remain unclear. We aimed to investigate the roles of astrocytes in the process of delayed neuronal death following transient forebrain ischemia. L-α-aminoadipic acid (L-α-AAA), an astrocyte-selective gliotoxin, was injected into the hippocampal CA3 region of rats through a cranial window to selectively damage astrocytes. Immunofluorescence staining of glial fibrillary acidic protein (GFAP) was used to evaluate the effect of L-α-AAA on astrocyte numbers. Three days after the L-α-AAA injection, transient forebrain ischemia was induced by a modification of the four-vessel occlusion procedure. Seven days after transient forebrain ischemia, hematoxylin-eosin staining was performed to reveal the morphology of hippocampal pyramidal neurons. In rats with ischemia and reperfusion, regional cerebral blood flow (rCBF) and change in intracellular Ca2+ concentration ([Ca2+]i) were separately measured in CA1 and CA3 regions. L-α-AAA injection significantly decreased the number of astrocytes in CA3, but did not affect the pattern of rCBF changes upon ischemia/reperfusion. Seven days after transient forebrain ischemia, in rats receiving L-α-AAA, delayed neuronal death comparable with that in CA1 was observed in the CA3 region. In addition, the pattern of increase in [Ca2+]i due to transient forebrain ischemia was completely changed in the hippocampal CA3. The loss of astrocytes induced a persistent increase in [Ca2+]i in the CA3 region following transient ischemia, similar to what is observed in the CA1 region. Our study indicates that astrocytes in the hippocampal CA3 region exert neuroprotective effects following transient forebrain ischemia and act by suppressing the intracellular Ca2+ overload. Furthermore, our study will most likely provide a new therapeutic strategy for brain ischemic diseases, targeted to astrocytes.
Highlights
In past decades, astrocytes have generally been considered as a supportive glial cell in the central nervous system (CNS)
To evaluate whether astrocytes participate in neuroprotection in the hippocampal CA3 region, a model with decreased astrocyte numbers in CA3 was created by local injection of L-α-aminoadipic acid (L-α-AAA)
To confirm decreased astrocyte numbers after L-α-AAA treatment, immunofluorescence staining for glial fibrillary acidic protein (GFAP), neuronal nuclear (NeuN), and DAPI staining were performed at day 3 and 10 after the injection, and the number of astrocytes (GFAP&DAPI + cells) in the hippocampal CA3 region was calculated
Summary
Astrocytes have generally been considered as a supportive glial cell in the central nervous system (CNS). In recent years, studies on astrocytes have shown that they play multiple roles in neuronal functioning, including both physiological and pathological processes (Sofroniew and Vinters, 2010; Clarke and Barres, 2013). In recent years, accumulating evidence has shown that astrocytes play an essential role in ischemic stroke. Most of these studies indicate that astrocytes exert neuroprotective effects through various mechanisms. A 2007 review showed that during brain ischemia, astrocytes may provide glycogen stores to support neurons and regulate the release of transmitters critical in ischemic brain damage, including glutamate, D-serine, and adenosine (Rossi et al, 2007). Astrocytes were reported to protect neurons by increasing neuronal glutathione levels (a response to oxidative stress), releasing protective factors such as erythropoietin, and regulating ionic homeostasis (Annunziato et al, 2013)
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