Individual differences in stereotypy and neuron subtype translatome with TrkB deletion.
Individual differences in stereotypy and neuron subtype translatome with TrkB deletion.
复制标题
刻板症和TrkB缺失的神经元亚型翻译组的个体差异。
DOI：
10.1038/s41380-020-0746-0
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发表时间：
2021-06
影响因子：
11
通讯作者：
Lobo MK
中科院分区：
文献类型：
--
作者：
Engeln M;Song Y;Chandra R;La A;Fox ME;Evans B;Turner MD;Thomas S;Francis TC;Hertzano R;Lobo MK
早发性神经精神疾病中出现的运动刻板印象与基底节直接通路活动失调有关。在啮齿动物和人类中，通过受损的神经元结构导致的网络连接中断都有牵连。然而，导致刻板印象中直接通路神经元连接中断的神经生物学机制仍然知之甚少。我们有一个从D1表达细胞(D1-Cre-flTrkB)中缺失原肌球蛋白受体激酶B(TrkB)受体的小鼠株系，其中一组动物表现出重复旋转和幼年发作的头部抽动。在这里，我们证明了这些行为可能与幼年和年轻成年小鼠通过化学发生抑制背侧纹状体D_1中棘神经元(D_1-MSN)减少旋转而异常的直接途径活动有关。利用相似基因动物的表型差异，然后我们通过核糖体相关mRNA的RNA测序来询问与重复行为相关的D1-MSN特异性翻译体组。详细的翻译组分析和多基因表达评估显示，刻板印象小鼠的神经元投射和突触结构相关基因发生了深刻的变化。神经元形态检查显示，重复行为的小鼠背侧纹状体d1-msn出现树突萎缩和树突棘丢失。总之，我们的结果揭示了D1-MSN中与表现出刻板行为的小鼠的形态适应相关的表型特异性分子变化。
Motor stereotypies occurring in early-onset neuropsychiatric diseases are associated with dysregulated basal ganglia direct-pathway activity. Disruptions in network connectivity through impaired neuronal structure have been implicated in both rodents and humans. However, the neurobiological mechanisms leading to direct-pathway neuron disconnectivity in stereotypy remain poorly understood. We have a mouse line with Tropomyosin receptor kinase B (TrkB) receptor deletion from D1-expressing cells (D1-Cre-flTrkB) in which a subset of animals shows repetitive rotations and head tics with juvenile onset. Here we demonstrate these behaviors may be associated with abnormal direct-pathway activity by reducing rotations using chemogenetic inhibition of dorsal striatum D1-medium spiny neurons (D1-MSNs) in both juvenile and young adult mice. Taking advantage of phenotypical differences in animals with similar genotype, we then interrogated the D1-MSN specific translatome associated with repetitive behavior by using RNA-sequencing of ribosome-associated mRNA. Detailed translatome analysis followed by multiplexed gene expression assessment revealed profound alterations in neuronal projection and synaptic structure related genes in stereotypy mice. Examination of neuronal morphology demonstrated dendritic atrophy and dendritic spine loss in dorsal striatum D1-MSNs from mice with repetitive behavior. Together, our results uncover phenotype-specific molecular alterations in D1-MSNs that relate to morphological adaptations in mice displaying stereotypy behavior.
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影响因子：
10.6
作者：
Engeln M;Mitra S;Chandra R;Gyawali U;Fox ME;Dietz DM;Lobo MK
通讯作者：
Lobo MK
影响因子：
30.8
作者：
Durand, Christelle M.;Betancur, Catalina;Bourgeron, Thomas
通讯作者：
Bourgeron, Thomas
影响因子：
5.3
作者：
Baydyuk M;Xu B
通讯作者：
Xu B
影响因子：
16.6
作者：
Besusso, Dario;Geibel, Mirjam;Minichiello, Liliana
通讯作者：
Minichiello, Liliana
影响因子：
25
作者：
Canales, JJ;Graybiel, AM
通讯作者：
Graybiel, AM