Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
Department of Neuroscience, University of Torino, Torino, Italy.
Biol Psychiatry. 2023 Jun 1;93(11):966-975. doi: 10.1016/j.biopsych.2022.11.018. Epub 2022 Dec 5.
Astrocytes control synaptic activity by modulating perisynaptic concentrations of ions and neurotransmitters including dopamine (DA) and, as such, could be involved in the modulating aspects of mammalian behavior.
We produced a conditional deletion of the vesicular monoamine transporter 2 (VMAT2) specifically in astrocytes (aVMTA2cKO mice) and studied the effects of the lack of VMAT2 in prefrontal cortex (PFC) astrocytes on the regulation of DA levels, PFC circuit functions, and behavioral processes.
We found a significant reduction of medial PFC (mPFC) DA levels and excessive grooming and compulsive repetitive behaviors in aVMAT2cKO mice. The mice also developed a synaptic pathology, expressed through increased relative AMPA versus NMDA receptor currents in synapses of the dorsal striatum receiving inputs from the mPFC. Importantly, behavioral and synaptic phenotypes were rescued by re-expression of mPFC VMAT2 and L-DOPA treatment, showing that the deficits were driven by mPFC astrocytes that are critically involved in developmental DA homeostasis. By analyzing human tissue samples, we found that VMAT2 is expressed in human PFC astrocytes, corroborating the potential translational relevance of our observations in mice.
Our study shows that impairment of the astrocytic control of DA in the mPFC leads to symptoms resembling obsessive-compulsive spectrum disorders such as trichotillomania and has a profound impact on circuit function and behaviors.
星形胶质细胞通过调节突触周围的离子和神经递质（包括多巴胺 [DA]）浓度来控制突触活动，因此可能参与了哺乳动物行为的调节方面。
我们特异性地在星形胶质细胞中产生了囊泡单胺转运体 2（VMAT2）的条件性缺失（aVMTA2cKO 小鼠），并研究了缺乏 VMAT2 对前额叶皮层（PFC）星形胶质细胞中 DA 水平、PFC 回路功能和行为过程的调节作用。
我们发现 aVMAT2cKO 小鼠的内侧前额叶皮层（mPFC）DA 水平显著降低，过度梳理和强迫性重复行为增加。这些小鼠还表现出突触病理学，表现为背侧纹状体接受来自 mPFC 的输入的突触中相对 AMPA 对 NMDA 受体电流增加。重要的是，通过重新表达 mPFC VMAT2 和 L-DOPA 治疗，挽救了行为和突触表型，表明缺陷是由 mPFC 星形胶质细胞驱动的，这些细胞在发育中的 DA 稳态中起着关键作用。通过分析人类组织样本，我们发现 VMAT2 在人类 PFC 星形胶质细胞中表达，证实了我们在小鼠中观察到的潜在转化相关性。
我们的研究表明，mPFC 中星形胶质细胞对 DA 的控制受损导致类似于强迫症谱系障碍的症状，如拔毛癖，并对回路功能和行为产生深远影响。
