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NO Enhances Presynaptic Currents During Cerebellar Mossy Fiber—Granule Cell LTP

¹ Department of Physiology and Pharmacology and Instituto Nazionale Fisica della Materia, Pavia University, 27100, Pavia ² Department of Evolutionary and Functional Biology, Parma University, 34100, Parma, Italy ³ Department of Neurophysiology, Brain Research Institute, Niigata University, 951-8585, Niigata, Japan

Submitted 22 April 2003; accepted in final form 14 May 2003

Nitric oxide (NO) is a candidate retrograde messenger in long-term potentiation (LTP). The NO metabolic pathway is expressed in the cerebellar granule cell layer but its physiological role remained unknown. In this paper we have investigated the role of NO in cerebellar mossy fiber–granule cell LTP, which has postsynaptic N-methyl-D-aspartate (NMDA) receptor-dependent induction. Pre- and postsynaptic current changes were simultaneously measured by using extracellular focal recordings, and NO release was monitored with an electrochemical probe in P21 rat cerebellar slices. High-frequency mossy fiber stimulation induced LTP and caused a significant NO release (6.2 ± 2.8 nM; n = 5) in the granular layer that was dependent on NMDA receptor as well as on nitric oxide synthase (NOS) activation. Preventing NO production by perfusing the NOS inhibitor 100 µM N^G-nitro-L-arginine (L-NNA), blocking extracellular NO diffusion by 10 µM MbO₂, or inhibiting the NO target guanylyl cyclase (sGC) with 10 µM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-dione (ODQ) prevented LTP. Moreover, the NO donor 10 µM 2-(N,N-diethylamino)-diazenolate-2-oxide·Na (DEA-NO) induced LTP, which was mutually occlusive with LTP generated by high-frequency stimulation, prevented by ODQ, and insensitive to NMDA channel blockade (50 µM APV + 25 µM 7-Cl-kyn) or interruption of mossy fiber stimulation. Thus NO is critical for LTP induction at the cerebellar mossy fiber–granule cell relay. Interestingly, LTP manipulations were accompanied by consensual changes in the presynaptic current, suggesting that NO acts as a retrograde signal-enhancing presynaptic terminal excitability.

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