P2Y1 receptors inhibit long-term depression in the prefrontal cortex.
Long-term depression (LTD) is a form of synaptic plasticity that may contribute to information storage in the central nervous system. Here we report that LTD can be elicited in layer 5 pyramidal neurons of the rat prefrontal cortex by pairing low frequency stimulation with a modest postsynaptic depolarization. The induction of LTD required the activation of both metabotropic glutamate receptors of the mGlu1 subtype and voltage-sensitive Ca(2+) channels (VSCCs) of the T/R, P/Q and N types, leading to the stimulation of intracellular inositol trisphosphate (IP3) receptors by IP3 and Ca(2+). The subsequent release of Ca(2+) from intracellular stores activated the protein phosphatase cascade involving calcineurin and protein phosphatase 1. The activation of purinergic P2Y(1) receptors blocked LTD. This effect was prevented by P2Y(1) receptor antagonists and was absent in mice lacking P2Y(1) but not P2Y(2) receptors. We also found that activation of P2Y(1) receptors inhibits Ca(2+) transients via VSCCs in the apical dendrites and spines of pyramidal neurons. In addition, we show that the release of ATP under hypoxia is able to inhibit LTD by acting on postsynaptic P2Y(1) receptors. In conclusion, these data suggest that the reduction of Ca(2+) influx via VSCCs caused by the activation of P2Y(1) receptors by ATP is the possible mechanism for the inhibition of LTD in prefrontal cortex.
Guzman
Segundo J
SJ
Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstr. 16-18, 04107 Leipzig, Germany. jose.guzman@physiologie.uni-freiburg.de
Schmidt
Hartmut
H
Franke
Heike
H
Krügel
Ute
U
Eilers
Jens
J
Illes
Peter
P
Gerevich
Zoltan
Z
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D005456:Fluorescent Dyes; D000860:Hypoxia / Q000503:physiopathology; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D015220:Calcium Channels; D005456:Fluorescent Dyes; D018094:Receptors, Metabotropic Glutamate; D058472:Receptors, Purinergic P2Y1; C104077:metabotropic glutamate receptor type 1; D000255:Adenosine Triphosphate; D002118:Calcium