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Emerging data indicate an important role for connexin43 (Cx43) in cognitive function, but there is a lack of direct evidence of the role of astroglial Cx43 in cognitive dysfunction in Alzheimer's disease (AD). Here we evaluated the expression pattern of Cx43 in AD and found progressive upregulation of the mRNA and protein levels of Cx43. Subsequently, we generated an astroglial Cx43 knockout (KO) AD mouse model by crossbreeding Gfap (glial fibrillary acidic protein)-Cx43 KO mice with APP/PS1 mice. Then we assessed the cognitive function of 12-month-old APP (amyloid precursor protein)/PS1 (presenilin 1)/Gfap-Cx43 KO mice, which demonstrated that the deletion of astroglial Cx43 significantly ameliorated cognitive dysfunction. To further investigate the underlying mechanisms, we evaluated amyloid plaque formation, astrogliosis, and synaptic function. The number and area of amyloid plaques were not altered, but GFAP expression was significantly decreased and the number of synapses was markedly upregulated. These results suggest that deletion of astroglial Cx43 in APP/PS1 mice did not affect the formation of amyloid plaques but depressed astrogliosis and upregulated synaptic function. Moreover, levels of critical modulators of astroglial activation were also notably reduced, but those of pro- and anti-inflammatory cytokines were not altered. Furthermore, Cx43 regulation of postsynaptic elements targets mainly NMDAR (N-methyl-d-aspartate). In addition, the prevention of AD pathology was reversed by Cx43 re-expression. In sum, specific deletion of astroglial Cx43 in APP/PS1 mice improved cognitive dysfunction by decreasing astrogliosis and increasing synaptic function without affecting amyloid plaque formation or the inflammatory response.