Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy.
Department of Translational Biomedicine and Neuroscience, University of Bari Aldo Moro, 70124, Bari, Italy.
Mol Psychiatry. 2024 Sep;29(9):2666-2677. doi: 10.1038/s41380-024-02527-3. Epub 2024 Mar 26.
Cognitive dysfunctions are core-enduring symptoms of schizophrenia, with important sex-related differences. Genetic variants of the DTBPN1 gene associated with reduced dysbindin-1 protein (Dys) expression negatively impact cognitive functions in schizophrenia through a functional epistatic interaction with Catechol-O-methyltransferase (COMT). Dys is involved in the trafficking of dopaminergic receptors, crucial for prefrontal cortex (PFC) signaling regulation. Moreover, dopamine signaling is modulated by estrogens via inhibition of COMT expression. We hypothesized a sex dimorphism in Dys-related cognitive functions dependent on COMT and estrogen levels. Our multidisciplinary approach combined behavioral-molecular findings on genetically modified mice, human postmortem Dys expression data, and in vivo fMRI during a working memory task performance. We found cognitive impairments in male mice related to genetic variants characterized by reduced Dys protein expression (p = 0.0001), as well as in male humans through a COMT/Dys functional epistatic interaction involving PFC brain activity during working memory (t(23) = -3.21; p = 0.004). Dorsolateral PFC activity was associated with lower working memory performance in males only (p = 0.04). Also, male humans showed decreased Dys expression in dorsolateral PFC during adulthood (p = 0.05). Female Dys mice showed preserved cognitive performances with deficits only with a lack of estrogen tested in an ovariectomy model (p = 0.0001), suggesting that genetic variants reducing Dys protein expression could probably become functional in females when the protective effect of estrogens is attenuated, i.e., during menopause. Overall, our results show the differential impact of functional variants of the DTBPN1 gene interacting with COMT on cognitive functions across sexes in mice and humans, underlying the importance of considering sex as a target for patient stratification and precision medicine in schizophrenia.
认知功能障碍是精神分裂症的核心持久症状，存在重要的性别相关差异。与低脑啡肽酶结合蛋白 1 蛋白（Dys）表达相关的 DTBPN1 基因遗传变异通过与儿茶酚-O-甲基转移酶（COMT）的功能上位性相互作用，对精神分裂症的认知功能产生负面影响。Dys 参与多巴胺能受体的运输，对前额叶皮层（PFC）信号调节至关重要。此外，多巴胺信号通过抑制 COMT 表达来调节雌激素。我们假设与 COMT 和雌激素水平相关的 Dys 相关认知功能存在性别二态性。我们的多学科方法结合了遗传修饰小鼠的行为-分子研究结果、人类死后 Dys 表达数据以及在工作记忆任务表现期间的体内 fMRI。我们发现，与具有降低 Dys 蛋白表达特征的遗传变异相关的雄性小鼠存在认知障碍（p = 0.0001），以及与涉及工作记忆期间 PFC 脑活动的 COMT/Dys 功能上位性相互作用的雄性人类存在认知障碍（t(23)=-3.21；p=0.004）。仅在男性中，背外侧前额叶皮层活动与较低的工作记忆表现相关（p=0.04）。此外，在成年期，男性人类的背外侧前额叶皮层中出现 Dys 表达减少（p=0.05）。雌性 Dys 小鼠表现出认知表现正常，仅在缺乏雌激素的情况下表现出缺陷，在卵巢切除术模型中进行了测试（p=0.0001），这表明当雌激素的保护作用减弱时，即在更年期，降低 Dys 蛋白表达的遗传变异可能在女性中变得具有功能。总体而言，我们的研究结果表明，在雄性和雌性小鼠和人类中，COMT 相互作用的 DTBPN1 基因功能变异对认知功能的影响不同，这突显了考虑性别作为精神分裂症患者分层和精准医学的目标的重要性。
