Zinc-mediated attenuation of hippocampal mossy fiber long-term potentiation induced by forskolin

The rise in presynaptic calcium induced by high-frequency stimulation activates the calcium-calmodulin-sensitive adenylyl cyclase (AC) 1 followed by the induction of long-term potentiation (LTP) at the hippocampal mossy fiber-CM synapse. Zinc is released with glutamate from mossy fiber terminals. However, the role of the zinc in mossy fiber LTP is controversial. In the present study, the mechanism of zinc-mediated attenuation of mossy fiber LIP was examined in that induced by forskolin, an AC activator. Mossy fiber LTP induced by tetanic stimulation (100 Hz for 1 s) was attenuated in the presence of 5 mu M ZnCl2, whereas that induced by forskolin under test stimulation (0.1 Hz) was not attenuated. Forskolin-induced mossy fiber LIP was attenuated by perfusion with 100 mu M ZnCl2 prior to the induction. However, the zinc (100 mu M) pre-perfusion did not attenuate mossy fiber LIP induced by Sp-cAMPS, an activator of protein kinase A, under test stimulation. Zinc is necessary to be taken up into mossy fiber boutons for effectively inhibiting AC activity. In hippocampal slices labeled with ZnAF-2 DA, a membrane-permeable zinc indicator, intracellular ZnAF-2 signal was increased during tetanic stimulation in the presence of 5 mu M ZnCl2, but not under test stimulation. Intracellular ZnAF-2 signal was increased under test stimulation in the presence of 100 mu M ZnCl2. These results suggest that zinc taken up into mossy fibers attenuates forskolin-induced mossy fiber LIP via inhibition of AC activity. The significance of endogenous zinc uptake by mossy fibers is discussed focused on tetanus-induced mossy fiber LIP. (C) 2010 Elsevier Ltd. All rights reserved.