Journal
JOURNAL OF NEUROSCIENCE
Volume 29, Issue 39, Pages 12115-12124Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3343-09.2009
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Funding
- National Institutes of Health [F31MH076422, F31DA023340, F32DA020427, RO1DA25875-2, HL059139, GM067773, DA015918, DA022269, MH66216]
- Edward Mallinckrodt Jr. Foundation
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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 D-2 receptors are negatively coupled to cAMP production, and activation of these receptors is required for endocannabinoid release and corticostriatal LTD. Recordings from striato-pallidal neurons indicated that this is mediated by AC5, because coactivation of D-2 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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