Corticostriatal Transmission Is Selectively Enhanced in Striatonigral Neurons with Postnatal Loss of Tsc1.
Corticostriatal Transmission Is Selectively Enhanced in Striatonigral Neurons with Postnatal Loss of Tsc1.
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DOI：
10.1016/j.celrep.2018.05.037
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发表时间：
2018-06-12
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;Ong SL;Bateup HS
mTORC1是一个整合细胞内和细胞外信号以调节多种细胞代谢过程的中央信号枢纽。mTORC1调节因子的突变导致与自闭症相关的神经发育障碍，其特征是重复的，不灵活的行为。这些行为可能是由于控制运动学习和习惯形成的纹状体回路的改变。然而，mTORC 1失调对纹状体神经元功能的影响在很大程度上尚不清楚。为了研究这一点，我们删除了mTORC1负调节Tsc 1从确定的纹状体黑质和纹状体苍白球神经元，并检查如何mTORC1活性的细胞自主上调影响其形态和生理。我们发现，Tsc 1的损失增加了纹状体黑质，但不是striatopallidal，神经元的兴奋性和选择性增强皮质纹状体突触传递。这些发现强调了mTORC1在以细胞类型和输入特异性方式调节纹状体活动中的关键作用，并暗示了神经精神疾病中纹状体黑质通路功能障碍。Benthall等人证明，出生后自闭症风险基因Tsc 1的缺失导致纹状体神经元形态和生理学的细胞类型特异性变化。他们发现，Tsc 1 KO纹状体黑质，但不是纹状体，神经元是过度兴奋的，并增强了皮层兴奋性突触传递的抑制变化的情况下。
mTORC1 is a central signaling hub that integrates intra- and extracellular signals to regulate a variety of cellular metabolic processes. Mutations in regulators of mTORC1 lead to neurodevelopmental disorders associated with autism, which is characterized by repetitive, inflexible behaviors. These behaviors may result from alterations in striatal circuits that control motor learning and habit formation. However, the consequences of mTORC1 dysregulation on striatal neuron function are largely unknown. To investigate this, we deleted the mTORC1 negative regulator Tsc1 from identified striatonigral and striatopallidal neurons and examined how cell-autonomous upregulation of mTORC1 activity affects their morphology and physiology. We find that loss of Tsc1 increases the excitability of striatonigral, but not striatopallidal, neurons and selectively enhances corticostriatal synaptic transmission. These findings highlight the critical role of mTORC1 in regulating striatal activity in a cell type- and input-specific manner, with implications for striatonigral pathway dysfunction in neuropsychiatric disease. In Brief Benthall et al. demonstrate that postnatal deletion of the autism-risk gene Tsc1 causes cell-type-specific changes in striatal neuron morphology and physiology. They find that Tsc1 KO striatonigral, but not striatopallidal, neurons are hyperexcitable and have enhanced cortical excitatory synaptic transmission in the absence of changes to inhibition.
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