Leggio G M, Torrisi S A, Mastrogiacomo R, Mauro D, Chisari M, Devroye C, Scheggia D, Nigro M, Geraci F, Pintori N, Giurdanella G, Costa L, Bucolo C, Ferretti V, Sortino M A, Ciranna L, De Luca M A, Mereu M, Managò F, Salomone S, Drago F, Papaleo F
Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
Department of Neuroscience and Brain Technologies, Genetics of Cognition laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163, Genova, Italy.
Mol Psychiatry. 2021 Apr;26(4):1272-1285. doi: 10.1038/s41380-019-0511-4. Epub 2019 Sep 6.
The dopamine D2 and D3 receptors are implicated in schizophrenia and its pharmacological treatments. These receptors undergo intracellular trafficking processes that are modulated by dysbindin-1 (Dys). Indeed, Dys variants alter cognitive responses to antipsychotic drugs through D2-mediated mechanisms. However, the mechanism by which Dys might selectively interfere with the D3 receptor subtype is unknown. Here, we revealed an interaction between functional genetic variants altering Dys and D3. Specifically, both in patients with schizophrenia and in genetically modified mice, concomitant reduction in D3 and Dys functionality was associated with improved executive and working memory abilities. This D3/Dys interaction produced a D2/D3 imbalance favoring increased D2 signaling in the prefrontal cortex (PFC) but not in the striatum. No epistatic effects on the clinical positive and negative syndrome scale (PANSS) scores were evident, while only marginal effects on sensorimotor gating, locomotor functions, and social behavior were observed in mice. This genetic interaction between D3 and Dys suggests the D2/D3 imbalance in the PFC as a target for patient stratification and procognitive treatments in schizophrenia.
多巴胺D2和D3受体与精神分裂症及其药物治疗有关。这些受体经历细胞内运输过程，该过程受失调素-1（Dys）调节。实际上，Dys变体通过D2介导的机制改变对抗精神病药物的认知反应。然而，Dys可能选择性干扰D3受体亚型的机制尚不清楚。在这里，我们揭示了改变Dys和D3的功能性基因变体之间的相互作用。具体而言，在精神分裂症患者和基因改造小鼠中，D3和Dys功能的同时降低与执行和工作记忆能力的改善有关。这种D3/Dys相互作用导致D2/D3失衡，有利于前额叶皮质（PFC）而非纹状体中D2信号的增加。对临床阳性和阴性症状量表（PANSS）评分没有明显的上位效应，而在小鼠中仅观察到对感觉运动门控、运动功能和社交行为的边缘效应。D3和Dys之间的这种基因相互作用表明，PFC中的D2/D3失衡是精神分裂症患者分层和认知治疗的一个靶点。
