Impaired long-term depression in P2X3 deficient mice is not associated with a spatial learning deficit.
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.
Wang
Yue
Y
Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD 21224, USA. wangyu@grc.nia.nih.gov
Mackes
Jennifer
J
Chan
Stephen
S
Haughey
Norman J
NJ
Guo
Zhihong
Z
Ouyang
Xin
X
Furukawa
Katsutoshi
K
Ingram
Donald K
DK
Mattson
Mark P
MP
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001923:Brain Chemistry / Q000235:genetics*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism / Q000503:physiopathology; D007859:Learning Disabilities / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D036881:Long-Term Synaptic Depression / Q000235:genetics*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000187:drug effects / Q000378:metabolism; D054645:Protein Phosphatase 1; D018048:Receptors, Purinergic P2 / Q000235:genetics*; D058477:Receptors, Purinergic P2X3; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; C546409:P2rx3 protein, mouse; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; D000255:Adenosine Triphosphate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1