Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling.
Striatal Synapse Degeneration and Dysfunction Are Reversed by Reactivation of Wnt Signaling.
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DOI：
10.3389/fnsyn.2021.670467
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发表时间：
2021
影响因子：
3.7
通讯作者：
Salinas PC
中科院分区：
文献类型：
--
作者：
Galli S;Stancheva SH;Dufor T;Gibb AJ;Salinas PC
纹状体中的突触变性与帕金森病和亨廷顿病（PD和HD）的早期阶段相关。然而，触发突触功能障碍和丧失的分子机制尚未完全了解。越来越多的证据表明，Wnt信号传导的缺陷引发成人大脑中的突触变性，并且该途径在神经退行性疾病中受到影响。在这里，我们表明，内源性Wnt信号是必不可少的抑制性突触的一个子集的纹状体中型棘神经元（MSN）的完整性。我们发现，在成年纹状体中特异性Wnt拮抗剂Dickkopf-1（Dkk 1）的诱导表达导致MSNs上抑制性突触的丧失，并影响D2-MSNs的突触传递。我们还发现，在突触大量丢失后，通过关闭Dkk 1表达重新激活Wnt通路，导致GABA能和多巴胺突触数量完全恢复。我们的研究结果还表明，Wnt通路的重新激活导致安非他明反应和运动功能的恢复。我们的研究将Wnt信号通路确定为突触变性后恢复神经元回路的潜在治疗靶点。
Synapse degeneration in the striatum has been associated with the early stages of Parkinson’s and Huntington’s diseases (PD and HD). However, the molecular mechanisms that trigger synaptic dysfunction and loss are not fully understood. Increasing evidence suggests that deficiency in Wnt signaling triggers synapse degeneration in the adult brain and that this pathway is affected in neurodegenerative diseases. Here, we demonstrate that endogenous Wnt signaling is essential for the integrity of a subset of inhibitory synapses on striatal medium spiny neurons (MSNs). We found that inducible expression of the specific Wnt antagonist Dickkopf-1 (Dkk1) in the adult striatum leads to the loss of inhibitory synapses on MSNs and affects the synaptic transmission of D2-MSNs. We also discovered that re-activation of the Wnt pathway by turning off Dkk1 expression after substantial loss of synapses resulted in the complete recovery of GABAergic and dopamine synapse number. Our results also show that re-activation of the Wnt pathway leads to a recovery of amphetamine response and motor function. Our studies identify the Wnt signaling pathway as a potential therapeutic target for restoring neuronal circuits after synapse degeneration.
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通过基础神经节电路的光遗传控制对帕金森运动行为的调节。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
ALBIN, RL;REINER, A;YOUNG, AB
通讯作者：
YOUNG, AB
影响因子：
5.3
作者：
Cepeda, Carlos;Galvan, Laurie;Levine, Michael S.
通讯作者：
Levine, Michael S.
影响因子：
5.7
作者：
Budnik V;Salinas PC
通讯作者：
Salinas PC
影响因子：
5.3
作者：
Koos, T;Tepper, JM;Wilson, CJ
通讯作者：
Wilson, CJ