Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice.
Transglutaminase 2 overexpression induces depressive-like behavior and impaired TrkB signaling in mice.
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DOI：
10.1038/mp.2016.145
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发表时间：
2017-05
影响因子：
11
通讯作者：
Pillai A
中科院分区：
文献类型：
--
作者：
Pandya CD;Hoda N;Crider A;Peter D;Kutiyanawalla A;Kumar S;Ahmed AO;Turecki G;Hernandez CM;Terry AV;Pillai A
5-羟色胺（5-HT）和脑源性神经营养因子（BDNF）是两种信号分子，在神经回路的发育和可塑性中起重要的调节作用，已知这些神经回路在抑郁症中被改变。然而，5-HT调节BDNF信号的机制尚不清楚。在本研究中，我们发现，5-HT治疗增加BDNF受体，Trk B（原肌球蛋白相关激酶B）在小鼠原代皮层神经元通过Rac 1（RAS相关的C3肉毒毒素底物1）依赖性机制。在慢性暴露于应激后，在小鼠前额叶皮层（PFC）中观察到转氨酶2（TG 2，其与5-HT转酰胺成Rac 1有关）水平的显著增加。我们还发现，TG 2水平增加，在死后PFC的抑郁症自杀主题相对于匹配的控制。此外，在小鼠中，神经元过度表达TG 2导致神经元萎缩和PFC中TrkB水平降低以及抑郁样表型。TG 2在小鼠皮层神经元中的过表达降低了TrkB水平，这是由于TrkB的内吞作用受损。通过病毒颗粒或药理学方法抑制TG 2可减弱由慢性不可预测的应激引起的行为缺陷。此外，TrkB在小鼠PFC中的过表达改善了TG 2过表达小鼠的抑郁样表型。综上所述，这些尸检和临床前研究结果确定TG 2作为改变TrkB表达和与慢性暴露于压力相关的抑郁样行为的关键介质，并表明TG 2可能代表抑郁症的新治疗靶点。
Serotonin (5-HT) and brain derived neurotrophic factor (BDNF) are two signaling molecules that play important regulatory roles in the development and plasticity of neural circuits that are known to be altered in depression. However, the mechanism by which 5-HT regulates BDNF signaling is unknown. In the present study, we found that 5-HT treatment increases BDNF receptor, TrkB (tropomyosin related kinase B) levels in mouse primary cortical neurons via a Rac1 (RAS-related C3 botulinum toxin substrate 1)-dependent mechanism. Significant increases in the levels of transglutaminase 2 (TG2, which is implicated in transamidation of 5-HT to Rac1) are observed in the mouse prefrontal cortex (PFC) following chronic exposure to stress. We also found that TG2 levels are increased in the postmortem PFC of depressed suicide subjects relative to matched controls. Moreover, in mice, neuronal overexpression of TG2 resulted in the atrophy of neurons and reduced levels of TrkB in the PFC as well as a depressive-like phenotype. Overexpression of TG2 in mouse cortical neurons reduced TrkB levels as a result of impaired endocytosis of TrkB. TG2 inhibition by either a viral particle or pharmacological approach attenuated behavioral deficits caused by chronic unpredictable stress. Moreover, the overexpression of TrkB in the mouse PFC ameliorated the depressive-like phenotype of TG2 overexpressed mice. Taken together, these postmortem and preclinical findings identify TG2 as a critical mediator of the altered TrkB expression and depressive-like behaviors associated with chronic exposure to stress and suggest that TG2 may represent a novel therapeutic target in depression.