Impaired long‐term depression in P2X3 deficient mice is not associated with a spatial learning deficit

• Published in: Journal of neurochemistry 2006-12, Vol.99 (5), p.1425-1434
• Main Authors: Wang, Yue, Mackes, Jennifer, Chan, Stephen, Haughey, Norman J., Guo, Zhihong, Ouyang, Xin, Furukawa, Katsutoshi, Ingram, Donald K., Mattson, Mark P.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Animals; Biological and medical sciences; Brain; Brain Chemistry - genetics; Calcium Signaling - drug effects; Calcium Signaling - physiology; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases - drug effects; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cells, Cultured; Central nervous system; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Electrophysiology; Enzyme Activation - drug effects; Enzyme Activation - physiology; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Hippocampus - metabolism; Hippocampus - physiopathology; Learning; Learning Disorders - genetics; Learning Disorders - metabolism; Learning Disorders - physiopathology; Long-Term Synaptic Depression - genetics; long‐term depression; long‐term potentiation; Male; Maze Learning - physiology; Medical sciences; Memory; Memory Disorders - genetics; Memory Disorders - metabolism; Memory Disorders - physiopathology; Mental depression; Mice; Mice, Knockout; Neurology; Neurons - drug effects; Neurons - metabolism; Neurotransmitters; P2X3KO mice; paired‐pulse facilitation; Phosphoprotein Phosphatases - drug effects; Phosphoprotein Phosphatases - metabolism; Protein Phosphatase 1; Proteins; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2X3; Rodents; Signal transduction; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Vertebrates: nervous system and sense organs; water maze
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2006.04198.x

The hippocampus is a brain region critical for learning and memory processes believed to result from long‐lasting changes in the function and structure of synapses. Recent findings suggest that ATP functions as a neurotransmitter or neuromodulator in the mammalian brain, where it activates several different types of ionotropic and G protein‐coupled ATP receptors that transduce calcium signals. However, the roles of specific ATP receptors in synaptic plasticity have not been established. Here we show that mice lacking the P2X3 ATP receptor (P2X3KO mice) exhibit abnormalities in hippocampal synaptic plasticity that can be restored by pharmacological modification of calcium‐sensitive kinase and phosphatase activities. Calcium imaging studies revealed an attenuated calcium response to ATP in hippocampal neurons from P2X3KO mice. Basal synaptic transmission, paired‐pulse facilitation and long‐term potentiation are normal at synapses in hippocampal slices from P2X3KO. However, long‐term depression is severely impaired at CA1, CA3 and dentate gyrus synapses. Long‐term depression can be partially rescued in slices treated with a protein phosphatase 1–2 A activator or by postsynaptic inhibition of calcium/calmodulin‐dependent protein kinase II. Despite the deficit in hippocampal long‐term depression, P2X3KO mice performed normally in water maze tests of spatial learning, suggesting that long‐term depression is not critical for this type of hippocampus‐dependent learning and memory.