Department of Psychiatry and Behavioral Sciences, University of Southern California, Los, Angeles, CA, USA.
Drug Discovery Research, Astellas Pharma, Inc, Tsukuba, Japan.
Neuroscience. 2022 Sep 1;499:104-117. doi: 10.1016/j.neuroscience.2022.07.023. Epub 2022 Jul 25.
Cognitive deficit remains an intractable symptom of schizophrenia, accounting for substantial disability. Despite this, little is known about the cause of cognitive dysfunction in schizophrenia. Recent studies suggest that schizophrenia patients show several changes in dentate gyrus structure and functional characteristic of immaturity. The immature dentate gyrus (iDG) has been replicated in several mouse models, most notably the CaMKIIα heterozygous mouse (CaMKIIα-hKO). The current study characterizes behavioral phenotypes of CaMKIIα-hKO mice and determines their neurophysiological profile using electroencephalogram (EEG) recording from hippocampus. CaMKIIα-hKO mice were hypoactive in home-cage environment; however, they displayed less anxiety-like phenotype, suggestive of impulsivity-like behavior. In addition, severe cognitive dysfunction was evident in CaMKIIα-hKO mice as examined by novel object recognition and contextual fear conditioning. Several EEG phenomena established in both patients and relevant animal models indicate key pathological changes associated with the disease, include auditory event-related potentials and time-frequency EEG oscillations. CaMKIIα-hKO mice showed altered event-related potentials characterized by an increase in amplitude of the N40 and P80, as well as increased P80 latency. These mice also showed increased power in theta range time-frequency measures. Additionally, CaMKIIα-hKO mice showed spontaneous bursts of spike wave activity, possibly indicating absence seizures. The GABAB agonist baclofen increased, while the GABAB antagonist CGP35348 and the T-Type Ca2 channel blocker Ethosuximide decreased spike wave burst frequency. None of these changes in event-related potentials or EEG oscillations are characteristic of those observed in general population of patients with schizophrenia; yet, CaMKIIα-hKO mice likely model a subpopulation of patients with schizophrenia.
认知缺陷仍然是精神分裂症的一种难以治愈的症状，导致了大量的残疾。尽管如此，对于精神分裂症认知功能障碍的原因知之甚少。最近的研究表明，精神分裂症患者的齿状回结构和不成熟的功能特征发生了几种变化。不成熟的齿状回（iDG）已在几种小鼠模型中得到复制，最著名的是 CaMKIIα 杂合子小鼠（CaMKIIα-hKO）。本研究描述了 CaMKIIα-hKO 小鼠的行为表型，并通过从海马体记录脑电图（EEG）来确定其神经生理特征。CaMKIIα-hKO 小鼠在其自身笼中表现出活动减少，但它们表现出较少的焦虑样表型，提示冲动样行为。此外，通过新物体识别和情景恐惧条件反射测试，明显显示 CaMKIIα-hKO 小鼠存在严重的认知功能障碍。在患者和相关动物模型中建立的几种 EEG 现象表明与疾病相关的关键病理变化，包括听觉事件相关电位和时频 EEG 振荡。CaMKIIα-hKO 小鼠的事件相关电位表现出振幅增加的特征，N40 和 P80 的振幅增加，以及 P80 潜伏期延长。这些小鼠在θ频段的时频测量中也表现出增加的功率。此外，CaMKIIα-hKO 小鼠表现出自发性尖波活动爆发，可能表明失神发作。GABAB 激动剂巴氯芬增加，而 GABAB 拮抗剂 CGP35348 和 T 型钙通道阻滞剂 Ethosuximide 降低了尖波爆发频率。这些事件相关电位或 EEG 振荡的变化都不是精神分裂症患者一般人群中观察到的特征；然而，CaMKIIα-hKO 小鼠可能模拟了精神分裂症患者的亚群。
