Aquaporin 4 (AQP4) is the predominant water channels in the brain of mammals. Our previous study has reported that AQP4 knockout induced sex-specific alterations in neurotransmission, indicating that AQP4 might regulate the interaction between sex hormones and neurotransmission. In the present study, we found that AQP4 knockout decreased the concentrations of estrogen and progestogen. Further study showed that exogenous estrogen decreased DA and 5-HT in cortex, reduced DA and 5-HT in striatum, but increased 5-HT in hippocampus in AQP4(+/+) male mice. However, in AQP4(-/-) male mice, exogenous estrogen almost did not alter the levels of neurotransmitters except for decreasing DA in cortex. In female mice, ovariectomy decreased DA in the striatum of AQP4(+/+) mice, but did not alter the levels of DA in AQP4(-/-) mice. These findings reveal for the first time that AQP4 regulates not only water and ion homeostasis but also the functions of ovarian hormone and neurotransmitter. (c) 2006 Elsevier Inc. All rights reserved.