Astrocytes secrete cytokines and neurotrophic factors to neurons, consistent with a neurosupportive role for astrocytes. However, in ischemic or metabolic insults, the function of astrocytic gap junctions composed mainly from connexin43 (Cx43) remains controversial. We have previously shown that heterozygous Cx43 null mice subjected to middle cerebral artery occlusion exhibited significantly enhanced stroke volume and apoptosis compared to wild-type mice. In this study, we used mice in which the human GFAP promoter-driven cre transgene deletes the floxed

Background and Purpose-Astrocytes may play a vital role in neuroprotection by providing energy substrates to neurons and regulating the concentration of K ϩ and neurotransmitters through gap junctions. Connexin 43 (Cx43) is one of the major gap junction proteins in astrocytes. We have shown that, after focal stroke, heterozygote Cx43 null (Cx43ϩ/Ϫ) mice exhibited larger infarction volumes than wild-type (Cx43ϩ/ϩ) mice. We explored the underlying mechanism by which gap junctional intercellular communication influences astrocytic activation and neuroprotection in ischemia. Methods-Both Cx43ϩ/Ϫ and Cx43ϩ/ϩ mice underwent right side permanent middle cerebral artery occlusion (MCAO).Mice were prepared by transcardial perfusion, and at 24 hours and 4 days after surgery, brains were prepared for immunohistochemistry or Western blot analysis. Results-Four days after MCAO, Cx43ϩ/Ϫ mice showed severe apoptosis in the penumbral lesion compared with Cx43ϩ/ϩ mice. The level of caspase-3 was significantly higher in the stroke lesion of Cx43ϩ/Ϫ mice than in Cx43ϩ/ϩ mice. Four days after MCAO, Cx43ϩ/Ϫ mice showed a significantly larger infarct volume but a smaller area of astrogliosis than did Cx43ϩ/ϩ mice. The penumbra of Cx43ϩ/Ϫ mice showed an increased level of Cx30 compared with Cx43ϩ/ϩ mice. Conclusions-Gap

Gap junctions are intercellular channels which directly connect the cytoplasm between neighboring cells. In the central nervous system (CNS) various kinds of cells are coupled by gap junctions, which play an important role in maintaining normal function. Neuronal gap junctions are involved in electrical coupling and may also contribute to the recovery of function after cell injury. Astrocytes are involved in the pathology of most neuronal disorders, including brain ischemia, Alzheimer's disease and epilepsy. In the pathology of brain tumors, gap junctions may be related to the degree of malignancy and metastasis. However, the role of connexins, gap junctions and hemichannels in the pathology of the diseases in the CNS is still ambiguous. Of increasing importance is the unraveling of the function of gap junctions in the neural cell network, involving neurons, astrocytes, microglia and oligodendrocytes. A better understanding of the role of gap junctions may contribute to the development of new therapeutic approaches to treating diseases of the CNS.

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