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The Journal of Neuroscience, September 30, 2009, 29(39):12115-12124; doi:10.1523/JNEUROSCI.3343-09.2009

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Behavioral/Systems/Cognitive
Adenylyl Cyclase Type 5 Contributes to Corticostriatal Plasticity and Striatum-Dependent Learning

Mazen A. Kheirbek,^1 * Jon P. Britt,^1 * Jeff A. Beeler,² Yoshihiro Ishikawa,⁴ Daniel S. McGehee,^1,3 and Xiaoxi Zhuang^1,2

¹Committee on Neurobiology and Departments of ²Neurobiology and ³Anesthesia and Critical Care, The University of Chicago, Chicago, Illinois 60637, and ⁴Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Newark, New Jersey 07103

Correspondence should be addressed to Daniel S. McGehee, Department of Anesthesia and Critical Care, The University of Chicago, 5841 S. Maryland Avenue, MC4028, Chicago, IL 60637. Email: dmcgehee{at}uchicago.edu

Dopamine (DA)-dependent corticostriatal plasticity is thought to underlie incremental procedural learning. A primary effector of striatal DA signaling is cAMP, yet its role in corticostriatal plasticity and striatum-dependent learning remains unclear. Here, we show that genetic deletion of a striatum-enriched isoform of adenylyl cyclase, AC5 knock-out (AC5KO), impairs two forms of striatum-dependent learning and corticostriatal synaptic plasticity. AC5KO mice were severely impaired in acquisition of a response strategy in the cross maze, a striatum-dependent task requiring a correct body turn to find a goal arm. In addition, AC5KO mice were impaired in acquisition of a motor skill, as assessed by the accelerated rotarod. Slice electrophysiology revealed a deficit in corticostriatal long-term depression (LTD) after high-frequency stimulation of tissue from AC5KO mice. LTD was rescued by activation of either presynaptic cannabinoid type 1 (CB₁) receptors or postsynaptic metabotropic glutamate receptors (mGluRs), suggesting a postsynaptic role of AC5–cAMP, upstream of endocannabinoid release. In striatopallidal-projecting medium spiny neurons, DA D₂ receptors are negatively coupled to cAMP production, and activation of these receptors is required for endocannabinoid release and corticostriatal LTD. Recordings from striatopallidal neurons indicated that this is mediated by AC5, because coactivation of D₂ and mGluRs could induce LTD in wild-type but not in AC5KO neurons. To further examine the role of cAMP in corticostriatal plasticity, we elevated cAMP in striatal neurons of wild-type mice via the recording electrode. Under these conditions, corticostriatal LTD was eliminated. Together, these data suggest an AC5–cAMP–endocannabinoid–CB₁ signaling pathway in corticostriatal plasticity and striatum-dependent learning.

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Received July 13, 2009; revised Aug. 5, 2009; accepted Aug. 6, 2009.

Correspondence should be addressed to Daniel S. McGehee, Department of Anesthesia and Critical Care, The University of Chicago, 5841 S. Maryland Avenue, MC4028, Chicago, IL 60637. Email: dmcgehee{at}uchicago.edu

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