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J. Biol. Chem., Vol. 281, Issue 33, 23464-23470, August 18, 2006

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Reactive Oxygen Species Mediate the Potentiating Effects of ATP on GABAergic Synaptic Transmission in the Immature Hippocampus^*

Victoria F. Safiulina, Ramil Afzalov, Leonard Khiroug, Enrico Cherubini, and Rashid Giniatullin¹

From the Neurobiology Department, International School for Advanced Studies, Via Beirut 2-4, 34014 Trieste, Italy and the Neuroscience Centre, University of Helsinki, PO Box 56, FIN-00014 Helsinki, Finland

Reactive oxygen species (ROS) constitute important signaling molecules in the central nervous system. They regulate a number of different functions both under physiological conditions and under pathological conditions. Here we tested the hypothesis that in the immature hippocampus ATP, the most diffuse neurotransmitter in the brain, modulates synaptic transmission via ROS. We show that ATP, acting on metabotropic P2Y₁ receptors, increased the frequency of GABA_A-mediated spontaneous postsynaptic currents (SPSCs) in CA3 principal cells, an effect that was prevented by the antioxidant N-acetyl-cysteine or by catalase, an enzyme that breaks down H₂O₂. The effect of ATP on SPSCs was mimicked by H₂O₂ or by the pro-oxidant, Fe²⁺, which, through the Fentol reaction, catalyzes the conversion of H₂O₂ into highly reactive hydroxyl radicals. MRS-2179, a P2Y₁ receptor antagonist, removed the facilitatory action of Fe²⁺ on SPSCs, suggesting that endogenous ATP acting on P2Y₁ receptors is involved in Fe²⁺-induced modulation of synaptic transmission. Imaging ROS with the H₂O₂-sensitive dye DCF revealed that ATP induces generation of peroxide in astrocytes via activation of P2Y₁ receptors coupled to intracellular calcium rise. Neither N-acetyl-cysteine nor catalase prevented Ca²⁺ transients induced by ATP in astrocytes. Since a single hippocampal astrocyte can contact many neurons, ATP-induced ROS signaling may control thousands of synapses. This may be crucial for information processing in the immature brain when GABAergic activity is essential for the proper wiring of the hippocampal network.

Received for publication, February 21, 2006 , and in revised form, June 16, 2006.

^* This work was supported by grants from Ministero Istruzione, Università, Ricerca (MIUR, PRIN 2005) (to E. C.), RFBR (Russia) (to V. F. S.), Telethon (to R. G.), the Center for International Mobility, Finland (to R. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 39-040-3787232; Fax: 39-040-3787528; E-mail: rashid{at}sissa.it.

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