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Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia

机译：精神分裂症基因小鼠模型中海马前额叶同步性受损

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Abnormalities in functional connectivity between brain areas have been postulated as an important pathophysiological mechanism underlying schizophrenia. In particular, macroscopic measurements of brain activity in patients suggest that functional connectivity between the frontal and temporal lobes may be altered. However, it remains unclear whether such dysconnectivity relates to the aetiology of the illness, and how it is manifested in the activity of neural circuits. Because schizophrenia has a strong genetic component, animal models of genetic risk factors are likely to aid our understanding of the pathogenesis and pathophysiology of the disease. Here we study Df(16)A~(+/-) mice, which model a microdele-tion on human chromosome 22 (22ql 1.2) that constitutes one of the largest known genetic risk factors for schizophrenia. To examine functional connectivity in these mice, we measured the synchronization of neural activity between the hippocampus and the pre-frontal cortex during the performance of a task requiring working memory, which is one of the cognitive functions disrupted in the disease. In wild-type mice, hippocampal-prefrontal synchrony increased during working memory performance, consistent with previous reports in rats. Df(16)A~(+/-) mice, which are impaired in the acquisition of the task, showed drastically reduced synchrony, measured both by phase-locking of prefrontal cells to hippocampal theta oscillations and by coherence of prefrontal and hippocampal local field potentials. Furthermore, the magnitude of hippocampal-prefrontal coherence at the onset of training could be used to predict the time it took the Df(16)A~(+/-) mice to learn the task and increased more slowly during task acquisition. These data suggest how the deficits in functional connectivity observed in patients with schizophrenia may be realized at the single-neuron level. Our findings further suggest that impaired long-range synchrony of neural activity is one consequence of the 22q11.2 deletion and may be a fundamental component of the pathophysiology underlying schizophrenia.
机译：大脑区域之间的功能连接异常被认为是精神分裂症的重要病理生理机制。特别是，对患者脑部活动的宏观测量表明，额叶和颞叶之间的功能连接性可能会改变。但是，目前尚不清楚这种不连通性是否与疾病的病因有关，以及它在神经回路的活动中如何表现出来。由于精神分裂症具有很强的遗传成分，因此遗传危险因素的动物模型可能有助于我们了解该疾病的发病机理和病理生理学。在这里，我们研究Df（16）A〜（+/-）小鼠，该小鼠对人类22号染色体（22ql 1.2）的微缺失进行建模，该染色体构成了已知的精神分裂症的最大遗传危险因素之一。为了检查这些小鼠中的功能连接性，我们在执行需要工作记忆的任务的过程中测量了海马体和前额叶皮层之间神经活动的同步性，这是该疾病中破坏性认知功能之一。在野生型小鼠中，海马-前额叶同步性在工作记忆表现期间增加，这与大鼠先前的报道一致。 Df（16）A〜（+/-）小鼠在完成任务时受到损害，其同步性急剧降低，这通过前额细胞对海马theta振荡的锁相以及前额和海马局部场的连贯性来衡量潜力。此外，训练开始时海马-前额叶连贯性的大小可用于预测Df（16）A〜（+/-）小鼠学习任务所花费的时间，并在任务获取过程中增加得更慢。这些数据表明如何在单神经元水平上实现精神分裂症患者中观察到的功能连通性缺陷。我们的发现进一步表明，神经活动的远程同步受损是22q11.2缺失的结果之一，并且可能是精神分裂症病理生理的基本组成部分。

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  • 来源
    《Nature》 |2010年第7289期|763-767|共5页
  • 作者

    Torfi Sigurdsson; Kimberly L. Stark; Maria Karayiorgou; Joseph A. Gogos; Joshua A. Gordon;

  • 作者单位

    Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA;

    rnDepartment of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA;

    rnDepartment of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA New York State Psychiatric Institute, New York, New York 10032, USA;

    rnDepartment of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA Department of Neuroscience, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA;

    rnDepartment of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA New York State Psychiatric Institute, New York, New York 10032, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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