Anoxia-induced hippocampal LTP is regeneratively produced by glutamate and nitric oxide from the neuro-glial-endothelial axis
Han-Ying Wang,
Hiroshi Takagi,
Patrick N. Stoney,
Anai Echeverria,
Bernd Kuhn,
Kuei-Sen Hsu,
Tomoyuki Takahashi
Affiliations
Han-Ying Wang
Cellular and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan; Academia Sinica, Institute of Biomedical Sciences, Taipei 115, Taiwan; Corresponding author
Hiroshi Takagi
Cellular and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan; Department of Neurosurgery, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
Patrick N. Stoney
Cellular and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan
Anai Echeverria
Optical Neuroimaging Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan
Bernd Kuhn
Optical Neuroimaging Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan
Kuei-Sen Hsu
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
Tomoyuki Takahashi
Cellular and Molecular Synaptic Function Unit, Okinawa Institute of Science and Technology Graduate University, Okinawa 904-0495, Japan; Corresponding author
Summary: Transient anoxia causes amnesia and neuronal death. This is attributed to enhanced glutamate release and modeled as anoxia-induced long-term potentiation (aLTP). aLTP is mediated by glutamate receptors and nitric oxide (·NO) and occludes stimulation-induced LTP. We identified a signaling cascade downstream of ·NO leading to glutamate release and a glutamate-·NO loop regeneratively boosting aLTP. aLTP in entothelial ·NO synthase (eNOS)-knockout mice and blocking neuronal NOS (nNOS) activity suggested that both nNOS and eNOS contribute to aLTP. Immunostaining result showed that eNOS is predominantly expressed in vascular endothelia. Transient anoxia induced a long-lasting Ca2+ elevation in astrocytes that mirrored aLTP. Blocking astrocyte metabolism or depletion of the NMDA receptor ligand D-serine abolished eNOS-dependent aLTP, suggesting that astrocytic Ca2+ elevation stimulates D-serine release from endfeet to endothelia, thereby releasing ·NO synthesized by eNOS. Thus, the neuro-glial-endothelial axis is involved in long-term enhancement of glutamate release after transient anoxia.
