Efimova Evgeniya V, Kuvarzin Saveliy R, Mor Mikael S, Katolikova Nataliia V, Shemiakova Taisiia S, Razenkova Valeria, Ptukha Maria, Kozlova Alena A, Murtazina Ramilya Z, Smirnova Daria, Veshchitskii Aleksandr A, Merkulyeva Natalia S, Volnova Anna B, Musienko Pavel E, Korzhevskii Dmitrii E, Budygin Evgeny A, Gainetdinov Raul R
Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.
Institute of Experimental Medicine, St. Petersburg, Russia.
Front Behav Neurosci. 2022 Apr 1;16:847410. doi: 10.3389/fnbeh.2022.847410. eCollection 2022.
Trace amines are a group of biogenic amines that are structurally and functionally close to classical monoamine neurotransmitters. Trace amine-associated receptors (TAARs) are emerging as promising targets for treating neuropsychiatric disorders. It has been documented that all TAARs, apart from TAAR1, function as olfactory receptors involved in sensing innate odors encoded by volatile amines. However, recently, brain expression and function of TAAR5 were also demonstrated. In this study, we assessed the behavior, brain neurochemistry, and electrophysiology changes in knock-out mice lacking Trace amine-associated receptor 2 (TAAR2) but expressing beta-Galactosidase mapping expression of TAAR2 receptors. As expected, we detected beta-Galactosidase staining in the glomerular layer of the olfactory bulb. However, we also found staining in the deeper layers of the olfactory bulb and several brain regions, including the hippocampus, cerebellum, cortex, raphe nuclei, hypothalamus, and habenula, indicating that TAAR2 receptors are not only expressed in the olfactory system but are also present in the limbic brain areas that receive olfactory input. In behavioral experiments, TAAR2 knock-out (TAAR2-KO) mice showed increased locomotor activity and less immobility in the forced swim test, with no changes in anxiety level. Furthermore, TAAR2-KO mice showed alterations in brain electrophysiological activity-particularly, decreased spectral power of the cortex and striatum in the 0, 9-20 Hz range. TAAR2-KO mice also had elevated tissue dopamine levels in the striatum and an increased dopaminergic neuron number in the Substantia Nigra. In addition, an increased brain-derived neurotrophic factor (BDNF) mRNA level in the striatum and Monoamine Oxidase B (MAO-B) mRNA level in the striatum and midbrain was found in TAAR2-KO mice. Importantly, TAAR2-KO mice demonstrated an increased neuroblast-like and proliferating cell number in the subventricular and subgranular zone, indicating increased adult neurogenesis. These data indicate that in addition to its role in the innate olfaction of volatile amines, TAAR2 is expressed in limbic brain areas and regulates the brain dopamine system, neuronal electrophysiological activity, and adult neurogenesis. These findings further corroborated observations in TAAR1-KO and TAAR5-KO mice, indicating common for TAAR family pattern of expression in limbic brain areas and role in regulating monoamine levels and adult neurogenesis, but with variable involvement of each subtype of TAAR receptors in these functions.
痕量胺是一类生物胺，其结构和功能与经典单胺神经递质相近。痕量胺相关受体（TAARs）正成为治疗神经精神疾病的有前景的靶点。据记载，除TAAR1外，所有TAARs均作为嗅觉受体发挥作用，参与感知由挥发性胺编码的固有气味。然而，最近TAAR5的脑表达和功能也得到了证实。在本研究中，我们评估了缺乏痕量胺相关受体2（TAAR2）但表达β-半乳糖苷酶以定位TAAR2受体表达的基因敲除小鼠的行为、脑神经化学和电生理变化。正如预期的那样，我们在嗅球的肾小球层检测到了β-半乳糖苷酶染色。然而，我们还在嗅球的更深层以及包括海马体、小脑、皮层、中缝核、下丘脑和缰核在内的几个脑区发现了染色，这表明TAAR2受体不仅在嗅觉系统中表达，也存在于接受嗅觉输入的边缘脑区。在行为实验中，TAAR2基因敲除（TAAR2-KO）小鼠在强迫游泳试验中表现出运动活性增加和不动时间减少，焦虑水平无变化。此外，TAAR2-KO小鼠的脑电生理活动出现改变，特别是在0.9-20Hz范围内，皮层和纹状体的频谱功率降低。TAAR2-KO小鼠纹状体中的组织多巴胺水平升高，黑质中的多巴胺能神经元数量增加。此外，在TAAR2-KO小鼠中发现纹状体中脑源性神经营养因子（BDNF）mRNA水平升高，纹状体和中脑中的单胺氧化酶B（MAO-B）mRNA水平升高。重要的是，TAAR2-KO小鼠在脑室下区和颗粒下区的神经母样细胞和增殖细胞数量增加，表明成体神经发生增加。这些数据表明，除了在挥发性胺的固有嗅觉中发挥作用外，TAAR2还在边缘脑区表达，并调节脑多巴胺系统、神经元电生理活动和成体神经发生。这些发现进一步证实了在TAAR1-KO和TAAR5-KO小鼠中的观察结果，表明TAAR家族在边缘脑区的表达模式以及在调节单胺水平和成体神经发生方面的作用具有共性，但TAAR受体的每个亚型在这些功能中的参与程度各不相同。
