Disturbances of novel object exploration and recognition in a chronic ketamine mouse model of schizophrenia
Disturbances of novel object exploration and recognition in a chronic ketamine mouse model of schizophrenia
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DOI：
10.1016/j.bbr.2017.06.013
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发表时间：
2017-08-14
影响因子：
2.7
通讯作者：
Roeper, Jochen
中科院分区：
文献类型：
--
作者：
Hauser, Maria Jelena;Isbrandt, Dirk;Roeper, Jochen
精神分裂症是一种慢性和毁灭性疾病，其总体终生风险为1%。虽然基于抑制2型多巴胺能受体（D2R）的抗精神病药物可以减轻精神分裂症的阳性症状，如幻觉和妄想，但目前的药物不能有效治疗精神分裂症的阴性症状（如动机降低）和认知症状（如工作记忆受损）。出现这种二分法的部分原因可能是我们对精神分裂症阴性症状和认知症状的病理生理学理解有限。除了遗传方法外，长期系统应用NMDA抑制剂（如氯胺酮）已被用于生成啮齿动物模型，这些模型显示出与阴性和认知症状相关的几种相关内表型，从而可能促进对潜在病理生理学的机制研究。在此背景下，先前的行为测试发现，在慢性nmda抑制剂精神分裂症啮齿动物模型中，新物体识别记忆的损伤是一个关键特征。然而，使用慢性氯胺酮小鼠模型，我们发现了更复杂的行为表型，包括新空间和新物体探索的缺陷，以及短期新物体识别记忆的缺陷。在我们的模型中，这些新颖性辨别的损伤与前额叶和海马区小蛋白表达的减少以及海马区新物体探索后早期直接基因c-fos的表达减少一致。我们的研究结果表明，长期服用氯胺酮的成年C57B16N小鼠在新奇探索和识别方面表现出联合损伤，这可能代表了精神分裂症的动机（阴性）和认知症状。
Schizophrenia is a chronic and devastating disease with an overall lifetime risk of 1%. While positive symptoms of schizophrenia such as hallucinations and delusions are reduced by antipsychotic medication based on the inhibition of type 2 dopaminergic receptors (D2R), negative symptoms (e.g. reduced motivation) and cognitive symptoms (e.g. impaired working memory) of schizophrenia are not effectively treated by current medication. This dichotomy might arise in part because of our limited understanding of the pathophysiology of negative and cognitive symptoms in schizophrenia. In addition to genetic approaches, chronic systemic application of NMDA inhibitors such as ketamine have been used to generate rodent models, which displayed several relevant endophenotypes related to negative and cognitive symptoms and might thus facilitate mechanistic studies into the underlying pathophysiology. In this context, previous behavioral testing identified impairments in novel object recognition memory as a key feature in chronic NMDA-inhibitor schizophrenia rodent models. Using a chronic ketamine mouse model, we have however identified are more complex behavioral phenotype including deficits in novel space and novel object exploration in combination deficits in short-term novel object recognition memory. These impairments in novelty discrimination are in line with prefrontal and hippocampal reductions in parvalbumin-expression as well as reduced expression of the early immediate gene c-fos after novel-object exploration in hippocampal areas in our model. Our results indicate that adult C57B16N mice chronically treated with ketamine display combined impairments in novelty exploration and recognition, which might represent both motivational (negative) and cognitive symptoms of schizophrenia.