Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
Department of Neurosciences, University of Mons, 6 Avenue du Champ de Mars, 7000 Mons, Belgium.
Biomolecules. 2023 Mar 11;13(3):516. doi: 10.3390/biom13030516.
Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the effect of the hyperactive DA system on the AMPA subunit composition, trafficking, and membrane localization in the prefrontal cortex (PFC). Taking advantage of dopamine transporter knock-out (DAT) rats, we found that DA overactivity reduced the translation of cortical AMPA receptors and their localization at both synaptic and extra-synaptic sites through, at least in part, altered intracellular vesicular sorting. Moreover, the reduced expression of AMPA receptor-specific anchoring proteins and structural markers, such as Neuroligin-1 and nCadherin, likely indicate a pattern of synaptic instability. Overall, these data reveal that a condition of hyperdopaminergia markedly alters the homeostatic plasticity of AMPA receptors, suggesting a general destabilization and depotentiation of the AMPA-mediated glutamatergic neurotransmission in the PFC. This effect might be functionally relevant for disorders characterized by elevated dopaminergic activity.
多巴胺 (DA) 和谷氨酸相互作用，影响神经兴奋性并促进突触可塑性。然而，对于这种串扰的分子机制知之甚少。由于 DA-AMPA 受体相互作用的改变可能维持病理性状态，我们工作的主要目的是评估过度活跃的 DA 系统对前额叶皮层 (PFC) 中 AMPA 亚基组成、转运和膜定位的影响。利用多巴胺转运蛋白敲除 (DAT) 大鼠，我们发现 DA 过度活跃通过至少部分改变细胞内囊泡分拣，减少皮质 AMPA 受体的翻译及其在突触和非突触部位的定位。此外，AMPA 受体特异性锚定蛋白和结构标记物（如 Neuroligin-1 和 nCadherin）的表达减少，可能表明存在突触不稳定的模式。总的来说，这些数据表明，高多巴胺能状态显著改变了 AMPA 受体的稳态可塑性，提示 PFC 中 AMPA 介导的谷氨酸能神经传递的普遍不稳定性和去极化。这种效应可能与多巴胺能活性升高的疾病有关。
