Adenylyl cyclase type 5 contributes to corticostriatal plasticity and striatum-dependent learning.
Adenylyl cyclase type 5 contributes to corticostriatal plasticity and striatum-dependent learning.
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DOI：
10.1523/jneurosci.3343-09.2009
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发表时间：
2009-09-30
期刊：
影响因子：
--
通讯作者：
Zhuang X
中科院分区：
文献类型：
--
作者：
Kheirbek MA;Britt JP;Beeler JA;Ishikawa Y;McGehee DS;Zhuang X
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 (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 LTD following 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 (MSNs), 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, as co-activation of D2 and mGluR receptors could induce LTD in WT, 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.
