Dopaminergic treatment weakens medium spiny neuron collateral inhibition in the parkinsonian striatum.
Dopaminergic treatment weakens medium spiny neuron collateral inhibition in the parkinsonian striatum.
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DOI：
10.1152/jn.00683.2016
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发表时间：
2017-03
影响因子：
2.5
通讯作者：
Wei Wei-Wei;Shengyuan Ding;F. Zhou
中科院分区：
文献类型：
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作者：
Wei Wei-Wei;Shengyuan Ding;F. Zhou
纹状体中棘神经元(MSN)对运动和认知功能都是至关重要的。MSN活动的一个潜在调节因素是来自邻近MSN的GABA能侧枝轴突输入。这些侧枝轴突终末进一步受到突触前多巴胺(DA)受体的调节，当帕金森病(PD)患者纹状体DA神经支配丢失时，DA受体可能会变得功能障碍。我们发现在正常和DA去神经支配的小鼠纹状体中，表达DA_1受体的MSN(D_1-MSN)和表达D_2受体的MSN(D_2-MSN)都形成了具有同型偏好的高速率单向侧支连接。此外，在去神经支配的纹状体中，尽管保留了同型偏爱、单向方向性和基本抑制强度，但DA以超敏的方式抑制了D2-msn-→-d2-msn侧支突触中GABA的释放。相反，对于D1msn起源的侧支连接，在正常纹状体中，d1激动剂促进了d1msnGABA的侧支抑制，而在帕金森病纹状体中，这种突触前D1R促进→释放的作用消失了。这些结果表明，在帕金森病纹状体内，多巴胺能抑制突触前的D2-MSN、→、D2-MSN的侧支抑制，解除对周围D2-MSN的抑制，而使D1-MSN的→、D1-MSN的侧支抑制因突触前D1受体易化而减弱，从而解除对周围的D1-MSN的抑制。总之，这些新发现的效应可以扰乱帕金森病纹状体的MSN回路，并可能有助于多巴胺能治疗诱导的PD运动和非运动行为的异常。值得注意的是，通过使用大型数据库，这项研究建立了邻近的同型纹状体棘突投射神经元有50%的机会形成单向侧支抑制连接，大大高于先前的估计。本研究还表明，多巴胺去神经支配可能改变突触前多巴胺受体的功能，使帕金森病的多巴胺能治疗可以减弱周围抑制，并可能减少纹状体输出的对比度，可能有助于多巴胺深刻的运动和非运动行为效应。
The striatal medium spiny neurons (MSNs) are critical to both motor and cognitive functions. A potential regulator of MSN activity is the GABAergic collateral axonal input from neighboring MSNs. These collateral axon terminals are further under the regulation of presynaptic dopamine (DA) receptors that may become dysfunctional when the intense striatal DA innervation is lost in Parkinson's disease (PD). We show that DA D1 receptor-expressing MSNs (D1-MSNs) and D2 receptor-expressing MSNs (D2-MSNs) each formed high-rate, one-way collateral connections with a homotypic preference in both normal and DA-denervated mouse striatum. Furthermore, whereas the homotypic preference, one-way directionality and the basal inhibitory strength were preserved, DA inhibited GABA release at the D2-MSN→D2-MSN collateral synapse in a supersensitive manner in the DA-denervated striatum. In contrast, for D1-MSN-originated collateral connections, whereas D1 agonism facilitated D1-MSN→D1-MSN collateral inhibition in the normal striatum, this presynaptic D1R facilitation of GABA release was lost in the parkinsonian striatum. These results indicate that in the parkinsonian striatum, dopaminergic treatment can presynaptically weaken the D2-MSN→D2-MSN collateral inhibition and disinhibit the surrounding D2-MSNs, whereas the D1-MSN→D1-MSN collateral inhibition is weakened by the loss of the presynaptic D1 receptor facilitation, disinhibiting the surrounding D1-MSNs. Together, these newly discovered effects can disrupt the MSN circuits in the parkinsonian striatum and may contribute to dopaminergic treatment-induced aberrant motor and nonmotor behaviors in PD.NEW & NOTEWORTHY With the use of a large database, this study establishes that neighboring homotypic striatal spiny projection neurons have a 50% chance to form one-way collateral inhibitory connection, a substantially higher rate than previous estimates. This study also shows that dopamine denervation may alter presynaptic dopamine receptor function such that dopaminergic treatment of Parkinson's disease can weaken the surround inhibition and may reduce the contrast of the striatal outputs, potentially contributing to dopamine's profound motor and nonmotor behavioral effects.