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The Journal of Neuroscience, April 30, 2008, 28(18):4736-4744; doi:10.1523/JNEUROSCI.1177-08.2008

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Behavioral/Systems/Cognitive
Ca-Stimulated Type 8 Adenylyl Cyclase Is Required for Rapid Acquisition of Novel Spatial Information and for Working/Episodic-Like Memory

Ming Zhang,^1,2 * Changjong Moon,^1,2,7 * Guy C.-K. Chan,⁶ Lan Yang,² Fei Zheng,^1,3 Alana C. Conti,⁵ Lisa Muglia,⁵ Louis J. Muglia,⁵ Daniel R. Storm,⁶ and Hongbing Wang^1,2,4

¹Department of Physiology, ²Neuroscience Program, ³Department of Biochemistry, and ⁴Cell and Molecular Biology Program, Michigan State University, East Lansing, Michigan 48824, ⁵Department of Pediatrics, Washington University, St. Louis, Missouri 63110, ⁶Department of Pharmacology, University of Washington, Seattle, Washington 98195, and ⁷Department of Veterinary Anatomy, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, South Korea

Correspondence should be addressed to either of the following: Hongbing Wang, Department of Physiology, Michigan State University, East Lansing, MI 48824, Email: wangho{at}msu.edu; or Daniel R. Storm, Department of Pharmacology, University of Washington, Seattle, WA 98195, Email: dstorm{at}u.washington.edu

Ca-stimulated adenylyl cyclases (ACs) transduce neuronal stimulation-evoked increase in calcium to the production of cAMP, which impinges on the regulation of many aspects of neuronal function. Type 1 and type 8 AC (AC1 and AC8) are the only ACs that are directly stimulated by Ca. Although AC1 function was implicated in regulating reference spatial memory, the function of AC8 in memory formation is not known. Because of the different biochemical properties of AC1 and AC8, these two enzymes may have distinct functions. For example, AC1 activity is regulated by both Ca and G-proteins. In contrast, AC8 is a pure Ca sensor. It is neither stimulated by G_s nor inhibited by G_i. Recent studies also suggested that AC1 and AC8 were differentially concentrated at different subcellular domains, implicating that Ca-stimulated signaling might be compartmentalized. In this study, we used AC8 knock-out (KO) mice and found behavioral deficits in memory retention for temporal dissociative passive avoidance and object recognition memory. When examined by Morris water maze, AC8 KO mice showed normal reference memory. However, the acquisition of newer spatial information was defective in AC8 KO mice. Furthermore, AC8 KO mice were severely impaired in hippocampus-dependent episodic-like memory when examined by the delayed matching-to-place task. Because AC8 is preferentially localized at the presynaptic active zone, our results suggest a novel role of presynaptic cAMP signaling in memory acquisition and retention, as well as distinct mechanisms underlying reference and working/episodic-like memory.

Key words: adenylyl cyclase; cAMP; synaptic plasticity; learning; memory; knock-out mice

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Received March 6, 2007; revised April 1, 2008; accepted April 1, 2008.

Correspondence should be addressed to either of the following: Hongbing Wang, Department of Physiology, Michigan State University, East Lansing, MI 48824, Email: wangho{at}msu.edu; or Daniel R. Storm, Department of Pharmacology, University of Washington, Seattle, WA 98195, Email: dstorm{at}u.washington.edu

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