Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning.
Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning.
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DOI：
10.1016/j.celrep.2021.109511
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发表时间：
2021-08-10
期刊：
影响因子：
8.8
通讯作者：
Bateup HS
中科院分区：
文献类型：
--
作者：
Benthall KN;Cording KR;Agopyan-Miu AHCW;Wong CD;Chen EY;Bateup HS
多发性硬化症（TSC）是一种神经发育障碍，通常表现为精神疾病，包括自闭症谱系障碍（ASD）。ASD的特征是受限的、重复的和不灵活的行为，这可能是由介导运动学习和动作选择的纹状体回路的异常活动引起的。为了测试是否改变纹状体活动有助于异常的运动行为的背景下，TSC，我们有条件地删除Tsc 1从直接或间接途径纹状体投射神经元（dSPN或iSPN，分别）。我们发现，dSPN特异性Tsc 1的丢失损害皮质-dSPN突触处的内源性大麻素介导的长期抑制（eCB-LTD），并强烈增强皮质纹状体突触驱动，这在iSPN中未观察到。dSPN-Tsc 1 KO而不是iSPN-Tsc 1 KO小鼠显示增强的运动学习，这是在几种ASD小鼠模型中观察到的表型。这些研究结果表明，dSPN是特别敏感的Tsc 1的损失，并表明，增强皮质纹状体激活可能有助于改变运动行为的TSC。Benthall等人表明，纹状体直接通路神经元（dSPN）的Tsc 1缺失会损害突触长期抑制，导致皮质驱动放电增加。增强的突触传递与dSPN-Tsc 1基因敲除小鼠的运动学习增加相关。这些发现对患有多发性硬化症的个体的运动行为改变有意义。
Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder that often presents with psychiatric conditions, including autism spectrum disorder (ASD). ASD is characterized by restricted, repetitive, and inflexible behaviors, which may result from abnormal activity in striatal circuits that mediate motor learning and action selection. To test whether altered striatal activity contributes to aberrant motor behaviors in the context of TSC, we conditionally deleted Tsc1 from direct or indirect pathway striatal projection neurons (dSPNs or iSPNs, respectively). We find that dSPN-specific loss of Tsc1 impairs endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses and strongly enhances corticostriatal synaptic drive, which is not observed in iSPNs. dSPN-Tsc1 KO, but not iSPN-Tsc1 KO, mice show enhanced motor learning, a phenotype observed in several mouse models of ASD. These findings demonstrate that dSPNs are particularly sensitive to Tsc1 loss and suggest that enhanced corticostriatal activation may contribute to altered motor behaviors in TSC. Benthall et al. show that loss of Tsc1 from striatal direct pathway neurons (dSPNs) impairs synaptic long-term depression, resulting in increased cortically driven firing. Enhanced synaptic transmission is associated with increased motor learning in dSPN-Tsc1 knockout mice. These findings have implications for altered motor behaviors in individuals with Tuberous Sclerosis Complex.
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影响因子：
8.8
作者：
Benthall KN;Ong SL;Bateup HS
通讯作者：
Bateup HS
影响因子：
6.1
作者：
Chevere-Torres, Itzamarie;Kaphzan, Hanoch;Bhattacharya, Aditi;Kang, Areum;Maki, Jordan M.;Gambello, Michael J.;Arbiser, Jack L.;Santini, Emanuela;Klann, Eric
通讯作者：
Klann, Eric
影响因子：
16.2
作者：
Arenkiel, Benjamin R.;Peca, Joao;Feng, Guoping
通讯作者：
Feng, Guoping
影响因子：
7.2
作者：
Graybiel, Ann M.;Grafton, Scott T.
通讯作者：
Grafton, Scott T.
影响因子：
4.8
作者：
Bergeron, Yan;Chagniel, Laure;Cyr, Michel
通讯作者：
Cyr, Michel