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The Journal of Neuroscience, April 1, 1999, 19(7):2500-2510

Adenylyl Cyclase Activation Modulates Activity-Dependent Changes in Synaptic Strength and Ca²⁺/Calmodulin-Dependent Kinase II Autophosphorylation

Michael Makhinson¹, Jennifer K. Chotiner¹, Joseph B. Watson^{1, 2}, and Thomas J. O'Dell^{1, 3}

¹ Interdepartmental Graduate Program for Neuroscience, ² Department of Psychiatry and Biobehavioral Sciences, and ³ Department of Physiology, University of California Los Angeles School of Medicine, Los Angeles, California 90095

Activation of the Ca²⁺- and calmodulin-dependent protein kinase II (CaMKII) and its conversion into a persistently activated form by autophosphorylation are thought to be crucial events underlying the induction of long-term potentiation (LTP) by increases in postsynaptic Ca²⁺. Because increases in Ca²⁺ can also activate protein phosphatases that oppose persistent CaMKII activation, LTP induction may also require activation of signaling pathways that suppress protein phosphatase activation. Because the adenylyl cyclase (AC)-protein kinase A signaling pathway may provide a mechanism for suppressing protein phosphatase activation, we investigated the effects of AC activators on activity-dependent changes in synaptic strength and on levels of autophosphorylated CaMKII (Thr²⁸⁶). In the CA1 region of hippocampal slices, briefly elevating extracellular Ca²⁺ induced an activity-dependent, transient potentiation of synaptic transmission that could be converted into a persistent potentiation by the addition of phosphatase inhibitors or AC activators. To examine activity-dependent changes in CaMKII autophosphorylation, we replaced electrical presynaptic fiber stimulation with an increase in extracellular K⁺ to achieve a more global synaptic activation during perfusion of high Ca²⁺ solutions. In the presence of the AC activator forskolin or the protein phosphatase inhibitor calyculin A, this treatment induced a LTP-like synaptic potentiation and a persistent increase in autophosphorylated CaMKII levels. In the absence of forskolin or calyculin A, it had no lasting effect on synaptic strength and induced a persistent decrease in autophosphorylated CaMKII levels. Our results suggest that AC activation facilitates LTP induction by suppressing protein phosphatases and enabling a persistent increase in the levels of autophosphorylated CaMKII.

Key words: hippocampal slices; long-term potentiation; Ca²⁺- and calmodulin-dependent kinase II; protein phosphatase; adenylyl cyclase; calcium

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Copyright © 1999 Society for Neuroscience  0270-6474/99/1972500-11$05.00/0

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