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The Journal of Neuroscience, 2001, 21:RC167:1-6

RAPID COMMUNICATION
FM1-43 Imaging Reveals cGMP-Dependent Long-Term Depression of Presynaptic Transmitter Release

Patric K. Stanton¹, Uwe Heinemann², and Wolfgang Müller²

¹ Departments of Neuroscience and Neurology, Albert Einstein College of Medicine, Bronx, New York 10461-1602, and ² Neuroscience Research Institute, Charité, Humboldt University, Berlin, D-10117, Germany

A persistent question concerning mechanisms underlying long-term, activity-dependent synaptic plasticity is whether the sites of alterations are presynaptic, postsynaptic, or both. Recently, we discovered a chemical method of inducing long-term depression (LTD) of synaptic strength at Schaffer collateral-CA1 synapses by simultaneously elevating [cGMP] and inhibiting cAMP-dependent protein kinase (PKA). Chemical LTD (CLTD) is activity-independent, occluded by stimulus-evoked LTD, and requires access of pharmacologic agents to presynaptic terminals. In the present study, we used fluorescence and two-photon imaging of presynaptic terminals with the fluorescent dye N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridinium dibromide (FM1-43) to determine directly if inducing CLTD is associated with a long-term reduction in transmitter release. In presynaptic Schaffer collateral-CA1 terminals of control hippocampal slices loaded with FM1-43, electrical stimulation (10 Hz/2 min) elicited a frequency-dependent destaining that peaked at 20% reduction in fluorescence. In contrast, when we first induced CLTD by a 30 min treatment of slices with the type V phosphodiesterase inhibitor zaprinast (20 µM) plus the PKA inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89; 10 µM), then washed for 60 min, the destaining of FM1-43 fluorescence evoked by the same stimulation was reduced to 4%. Treatment and washout of slices with either drug singly had a significantly smaller effect on stimulus-evoked FM1-43 destaining. Only CLTD was associated with virtually complete suppression of stimulus-evoked FM1-43 release, the first direct evidence for at least one form of LTD being mediated by persistent reduction of presynaptic transmitter release.

Key words: CA1; cGMP; hippocampus; long-term depression; presynaptic terminal; Schaffer collateral; PKA; PKG; transmitter release

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Copyright © Society for Neuroscience  0270-6474//$05.00/0

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