Chronic ceftriaxone treatment rescues hippocampal memory deficit in AQP4 knockout mice via activation of GLT-1.

Aquaporin-4 (AQP4) is the predominant water channel protein in the mammalian brain, and is mainly expressed in astrocytes. Besides its important role in water transport across the blood-brain barrier, our present study demonstrated that AQP4 deficiency impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent memory formation, accompanied by the increase in extracellular glutamate concentration and N-methyl-d-aspartate (NMDA) receptor-mediated currents in hippocampal dentate gyrus (DG) region. The impairment of LTP and memory formation of AQP4 knockout (KO) mice was mediated by the downregulation of glutamate transporter-1 (GLT-1) expression/function, since it can be rescued by β-lactam antibiotic ceftriaxone (Cef), a potent GLT-1 stimulator. These results suggest that AQP4 functions as the modulator of synaptic plasticity and memory, and chronic Cef treatment rescues hippocampal memory deficit induced by AQP4 knockout.