WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine
WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine
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DOI：
10.1073/pnas.1621185114
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发表时间：
2017-02-07
影响因子：
11.1
通讯作者：
Kim, Yong
中科院分区：
文献类型：
--
作者：
Ceglia, Ilaria;Lee, Ko-Woon;Kim, Yong
Wiskott-Aldrich 综合征蛋白 (WASP) 家族 verprolin 同源蛋白 1 (WAVE1) 调节肌动蛋白相关蛋白 2/3 (Arp2/3) 复合物介导的肌动蛋白聚合。我们前期的研究发现WAVE1在大脑中被Cdk5介导的磷酸化抑制，并在树突棘形态的调节中发挥作用。在此，我们报告说，表达 D1 多巴胺受体 (D1-KO) 的神经元中 WAVE1 被敲除 (KO) 的小鼠，而不是表达 D2 多巴胺受体 (D2-KO) 的神经元中 WAVE1 被敲除的小鼠，表现出与可卡因相关的位置偏好显着下降。与野生型 (WT) 和 WAVE1 D2-KO 小鼠相比，可卡因诱导的敏化运动行为在 WAVE1 D1-KO 小鼠中并未维持。长期服用可卡因并戒断后，急性可卡因激发诱导纹状体中 WAVE1 激活，并通过去磷酸化进行评估。可卡因诱导的 WAVE1 去磷酸化通过同时给予 D1 多巴胺受体或 NMDA 谷氨酸受体拮抗剂而减弱。在慢性可卡因暴露和戒断后对可卡因进行急性激发时，我们还在 WT 小鼠（但在 WAVE1 D1-KO 小鼠中）中观察到伏隔核中表达 D1 多巴胺受体 (D1-MSN) 的中型多棘投射神经元的树突棘密度降低和兴奋性突触后 AMPA 受体电流频率降低。这些结果表明，WAVE1 选择性地参与可卡因诱发的神经元活动介导的谷氨酸能突触反馈调节中的 D1-MSN。
Wiskott-Aldrich syndrome protein (WASP) family verprolin homologous protein 1 (WAVE1) regulates actin-related protein 2/3 (Arp2/3) complex-mediated actin polymerization. Our previous studies have found WAVE1 to be inhibited by Cdk5-mediated phosphorylation in brain and to play a role in the regulation of dendritic spine morphology. Herewe report thatmice inwhich WAVE1was knocked out (KO) in neurons expressing the D1 dopamine receptor (D1-KO), but not mice where WAVE1 was knocked out in neurons expressing the D2 dopamine receptor (D2-KO), exhibited a significant decrease in place preference associated with cocaine. In contrast to wild-type (WT) and WAVE1 D2-KO mice, cocaine-induced sensitized locomotor behavior was not maintained in WAVE1 D1-KO mice. After chronic cocaine administration and following withdrawal, an acute cocaine challenge induced WAVE1 activation in striatum, which was assessed by dephosphorylation. The cocaine-induced WAVE1 dephosphorylation was attenuated by coadministration of either a D1 dopamine receptor or NMDA glutamate receptor antagonist. Upon an acute challenge of cocaine following chronic cocaine exposure and withdrawal, we also observed in WT, but not in WAVE1 D1-KO mice, a decrease in dendritic spine density and a decrease in the frequency of excitatory postsynaptic AMPA receptor currents in medium spiny projection neurons expressing the D1 dopamine receptor (D1-MSNs) in the nucleus accumbens. These results suggest that WAVE1 is involved selectively in D1-MSNs in cocaine-evoked neuronal activitymediated feedback regulation of glutamatergic synapses.