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.
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We thank Dr. M. Morini, D. Cantatore, R. Navone, G. Pruzzo, A. Parodi, B. Chiarenza, A. Monteforte, and C. Chiabrera for technical support. This work was supported by funding from the Istituto Italiano di Tecnologia, the University of Catania, the Brain and Behavior Research Foundation (2015 NARSAD 23234), and the Compagnia di San Paolo (2015–0321).
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Leggio, G.M., Torrisi, S.A., Mastrogiacomo, R. et al. The epistatic interaction between the dopamine D3 receptor and dysbindin-1 modulates higher-order cognitive functions in mice and humans. Mol Psychiatry (2019). https://doi.org/10.1038/s41380-019-0511-4
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