Guzmán, JoséIST Austria; Schmidt, Hartmut; Franke, Heike; Krügel, Ute; Eilers, Jens; Illes, Peter; Gerevich, Zoltan
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.
The financial support of the Deutsche Forschungsgemeinschaft (IL 20/12-1, KI 677/2-4) is gratefully acknowledged. We thank B. H. Koller (Department of Genetics and Molecular Biology, University of North Carolina at Chapel Hill, NC, USA) for the generous supply of P2Y1−/− and P2Y2−/− mice. We are grateful to Dr. A. Schulz for reanalysing the genotype of the P2Y1−/− mice. The authors thank P. Jonas and U. Heinemann for many helpful comments and A-K. Krause, L Feige and M. Eberts for their excellent technical support.
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Guzmán J, Schmidt H, Franke H, et al. P2Y1 receptors inhibit long-term depression in the prefrontal cortex. Neuropharmacology. 2010;59(6):406-415. doi:10.1016/j.neuropharm.2010.05.013
Guzmán, J., Schmidt, H., Franke, H., Krügel, U., Eilers, J., Illes, P., & Gerevich, Z. (2010). P2Y1 receptors inhibit long-term depression in the prefrontal cortex. Neuropharmacology. Elsevier. https://doi.org/10.1016/j.neuropharm.2010.05.013
Guzmán, José, Hartmut Schmidt, Heike Franke, Ute Krügel, Jens Eilers, Peter Illes, and Zoltan Gerevich. “P2Y1 Receptors Inhibit Long-Term Depression in the Prefrontal Cortex.” Neuropharmacology. Elsevier, 2010. https://doi.org/10.1016/j.neuropharm.2010.05.013.
J. Guzmán et al., “P2Y1 receptors inhibit long-term depression in the prefrontal cortex.,” Neuropharmacology, vol. 59, no. 6. Elsevier, pp. 406–415, 2010.
Guzmán J, Schmidt H, Franke H, Krügel U, Eilers J, Illes P, Gerevich Z. 2010. P2Y1 receptors inhibit long-term depression in the prefrontal cortex. Neuropharmacology. 59(6), 406–415.
Guzmán, José, et al. “P2Y1 Receptors Inhibit Long-Term Depression in the Prefrontal Cortex.” Neuropharmacology, vol. 59, no. 6, Elsevier, 2010, pp. 406–15, doi:10.1016/j.neuropharm.2010.05.013.