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The Journal of Neuroscience, May 14, 2008, 28(20):5159-5168; doi:10.1523/JNEUROSCI.5317-07.2008
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Cellular/Molecular
A Specific Role for Ca2+-Dependent Adenylyl Cyclases in Recovery from Adaptive Presynaptic Silencing
Krista L. Moulder,1 Xiaoping Jiang,1 ChunYun Chang,5 Amanda A. Taylor,1 Ann M. Benz,1 Alana C. Conti,2 Louis J. Muglia,2,3 andSteven Mennerick1,4 Departments of 1Psychiatry, 2Pediatrics, 3Developmental Biology, and 4Anatomy and Neurobiology, and 5Graduate Program in Development, Washington University School of Medicine, St. Louis, Missouri 63110
Correspondence should be addressed to Dr. Krista L. Moulder, Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Box 8134, St. Louis, MO 63110. Email: moulderk{at}psychiatry.wustl.edu
Glutamate generates fast postsynaptic depolarization throughout the CNS. The positive-feedback nature of glutamate signaling likely necessitates flexible adaptive mechanisms that help prevent runaway excitation. We have previously explored presynaptic adaptive silencing, a form of synaptic plasticity produced by ongoing neuronal activity and by strong depolarization. Unsilencing mechanisms that maintain active synapses and restore normal function after adaptation are also important, but mechanisms underlying such presynaptic reactivation remain unexplored. Here we investigate the involvement of the cAMP pathway in the basal balance between silenced and active synapses, as well as the recovery of baseline function after depolarization-induced presynaptic silencing. Activation of the cAMP pathway activates synapses that are silent at rest, and pharmacological inhibition of cAMP signaling silences basally active synapses. Adenylyl cyclase (AC) 1 and AC8, the major Ca2+-sensitive AC isoforms, are not crucial for the baseline balance between silent and active synapses. In cells from mice doubly deficient in AC1 and AC8, the baseline percentage of active synapses was only modestly reduced compared with wild-type synapses, and forskolin unsilencing was similar in the two genotypes. Nevertheless, after strong presynaptic silencing, recovery of normal function was strongly inhibited in AC1/AC8-deficient synapses. The entire recovery phenotype of the double null was reproduced in AC8-deficient but not AC1-deficient cells. We conclude that, under normal conditions, redundant cyclase activity maintains the balance between presynaptically silent and active synapses, but AC8 plays a particularly important role in rapidly resetting the balance of active to silent synapses after adaptation to strong activity.
Key words: exocytosis; homeostasis; synaptic strength; epilepsy; cAMP; glutamate
Received Nov. 30, 2007; revised April 10, 2008; accepted April 10, 2008.
Correspondence should be addressed to Dr. Krista L. Moulder, Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Box 8134, St. Louis, MO 63110. Email: moulderk{at}psychiatry.wustl.edu
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