Direct excitation of inhibitory interneurons by extracellular ATP mediated by P2Y1 receptors in the hippocampal slice.
ATP is an important cell-to-cell signaling molecule mediating the interactions between astrocytes and neurons in the CNS. In the hippocampal slices, ATP suppresses excitatory transmission mostly through activation of adenosine A1 receptors, because the ectoenzyme activity for the extracellular breakdown of ATP to adenosine is high in slice preparations in contrast to culture environments. Because the hippocampus is also rich in the expression of P2 receptors activated specifically by ATP, we examined whether ATP modulates neuronal excitability in the acute slice preparations independently of adenosine receptors. Although ATP decreased the frequency of spontaneously occurring EPSCs in the CA3 pyramidal neurons through activation of adenosine A1 receptors, ATP concurrently increased the frequency of IPSCs in a manner dependent on action potential generation. This effect was mediated by P2Y1 receptors because (1) 2-methylthio-ATP (2meSATP) was the most potent agonist, (2) 2'-deoxy-N6-methyladenosine-3',5'-bisphosphate diammonium (MRS2179) abolished this effect, and (3) this increase in IPSC frequency was not observed in the transgenic mice lacking P2Y1 receptor proteins. Application of 2meSATP elicited MRS2179-sensitive time- and voltage-dependent inward currents in the interneurons, which depolarized the cell to firing threshold. Also, it increased [Ca2+]i in both astrocytes and interneurons, but, unlike the former effect, the latter was entirely dependent on Ca2+ entry. Thus, in hippocampal slices, in addition to activating A1 receptors of the excitatory terminals after being converted to adenosine, ATP activates P2Y1 receptors in the interneurons, which is linked to activation of unidentified excitatory conductance, through mechanisms distinct from those in the astrocytes.
Kawamura
Masahito
M
Laboratory of Neurophysiology, Department of Neuroscience, Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan.
Gachet
Christian
C
Inoue
Kazuhide
K
Kato
Fusao
F
D000200:Action Potentials / Q000187:drug effects; D000241:Adenosine / Q000502:physiology; D058907:Adenosine A1 Receptor Agonists; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D045604:Extracellular Fluid; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009928:Organ Specificity; D018408:Patch-Clamp Techniques; D058910:Purinergic P2 Receptor Agonists; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000187:drug effects; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000502:physiology; D018048:Receptors, Purinergic P2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D058472:Receptors, Purinergic P2Y1; D013045:Species Specificity; D013873:Thionucleotides / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; D018377:Neurotransmitter Agents; C546383:P2ry1 protein, mouse; D058910:Purinergic P2 Receptor Agonists; D043682:Receptor, Adenosine A1; D017661:Receptors, Presynaptic; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D013873:Thionucleotides; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000241:Adenosine; C008501:2-methylthio-ATP