Neurobiology & Mitochondrial Key Laboratory, Effective & Toxicity Monitoring Innovative Practice Center for Food Pharmaceutical Specialty, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, PR China.
Neurobiology & Mitochondrial Key Laboratory, Effective & Toxicity Monitoring Innovative Practice Center for Food Pharmaceutical Specialty, School of Pharmacy, Jiangsu University, Zhenjiang, 212013, PR China.
Eur J Pharmacol. 2023 Oct 5;956:175940. doi: 10.1016/j.ejphar.2023.175940. Epub 2023 Aug 2.
Multiple genome studies have discovered that variation in deleted in colorectal carcinoma (Dcc) at transcription and translation level were associated with the occurrences of psychiatric disorders. Yet, little is known about the function of Dcc in schizophrenia (SCZ)-related behavioral abnormalities and the efficacy of antipsychotic drugs in vivo. Here, we used an animal model of prefrontal cortex-specific knockdown (KD) of Dcc in adult C57BL/6 mice to study the attention deficits and impaired locomotor activity. Our results supported a critical role of Dcc deletion in SCZ-related behaviors. Notably, olanzapine rescued the SCZ-related behaviors in the MK801-treated mice but not in the cortex-specific Dcc KD mice, indicating that Dcc play a critical in the mechanism of antipsychotic effects of olanzapine. Knockdown of Dcc in prefrontal cortex results in glutamatergic dysfunction, including defects in glutamine synthetase and postsynaptic maturation. As one of the major risk factors of the degree of antipsychotic response, Dcc deletion-induced glutamatergic dysfunction may be involved in the underlying mechanism of treatment resistance of olanzapine. Our findings identified Dcc deletion-mediated SCZ-related behavioral defects, which serve as a valuable animal model for study of SCZ and amenable to targeted investigations in mechanistic hypotheses of the mechanism underlying glutamatergic dysfunction-induced antipsychotic treatment resistance.
多项基因组研究发现，转录和翻译水平的结直肠癌缺失基因（Dcc）变异与精神疾病的发生有关。然而，关于 Dcc 在精神分裂症（SCZ）相关行为异常中的作用以及体内抗精神病药物的疗效知之甚少。在这里，我们使用成年 C57BL/6 小鼠前额叶皮层特异性 Dcc 敲低（KD）的动物模型来研究注意力缺陷和运动活动受损。我们的研究结果支持 Dcc 缺失在 SCZ 相关行为中的关键作用。值得注意的是，奥氮平挽救了 MK801 处理小鼠的 SCZ 相关行为，但不能挽救皮层特异性 Dcc KD 小鼠的 SCZ 相关行为，表明 Dcc 在奥氮平的抗精神病作用机制中起关键作用。Dcc 在前额叶皮层中的敲低导致谷氨酸能功能障碍，包括谷氨酰胺合成酶和突触后成熟缺陷。作为抗精神病反应程度的主要危险因素之一，Dcc 缺失诱导的谷氨酸能功能障碍可能与奥氮平治疗抵抗的潜在机制有关。我们的研究结果确定了 Dcc 缺失介导的 SCZ 相关行为缺陷，为研究 SCZ 提供了一个有价值的动物模型，并适用于研究谷氨酸能功能障碍诱导的抗精神病治疗抵抗的潜在机制的机制假设。
