Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia.
Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia.
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脑区之间功能连接的缺失被认为是精神分裂症的重要病理生理机制。特别是，对患者大脑活动的宏观测量表明，额叶和颞叶之间的功能连接可能会改变。然而，目前尚不清楚这种连接障碍是否与疾病的病因有关，以及它如何表现在神经回路的活动中。由于精神分裂症有很强的遗传成分，遗传风险因素的动物模型可能有助于我们了解疾病的发病机制和病理生理学。在这里，我们研究了Df（16）A+/−小鼠，它模拟了人类22号染色体（22q11.2）上的微缺失，该微缺失构成了精神分裂症最大的已知遗传风险因素之一。为了检查这些小鼠的功能连接，我们测量了在执行需要工作记忆的任务期间海马和前额叶皮质之间神经活动的同步，这是疾病中中断的认知功能之一。在野生型小鼠中，在工作记忆表现期间，前额叶-前额叶同步性增加，与之前在大鼠中的报道一致。通过前额叶细胞与海马theta振荡的相位锁定以及前额叶和海马局部场电位的一致性来测量，在任务获取方面受损的Df（16）A+/−小鼠显示出显著降低的同步性。此外，训练开始时的大脑前额叶-前额叶连贯性的大小可以用来预测Df（16）A+/−小鼠学习任务所需的时间，并且在任务获取过程中增加得更慢。这些数据表明，在精神分裂症患者中观察到的功能连接缺陷可能是在单神经元水平上实现的。我们的研究结果进一步表明，受损的远程同步的神经活动是22q11.2缺失的后果之一，可能是精神分裂症的病理生理基础的基本组成部分。
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 microdeletion on human chromosome 22 (22q11.2) 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 prefrontal 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.
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影响因子：
30.8
作者：
Xu, Bin;Roos, J. Louw;Karayiorgou, Maria
通讯作者：
Karayiorgou, Maria
影响因子：
25
作者：
Mukai, Jun;Dhilla, Alefiya;Drew, Liam J.;Stark, Kimberly L.;Cao, Luxiang;MacDermott, Amy B.;Karayiorgou, Maria;Gogos, Joseph A.
通讯作者：
Gogos, Joseph A.
DOI：
10.1016/j.molbrainres.2004.09.029
发表时间：
2004-12-20
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Karayiorgou, M;Gogos, JA
通讯作者：
Gogos, JA
影响因子：
25
作者：
Paterlini, M;Zakharenko, SS;Gogos, JA
通讯作者：
Gogos, JA
影响因子：
2.6
作者：
Kates, Wendy R.;Krauss, Beth R.;Shprintzen, Robert J.
通讯作者：
Shprintzen, Robert J.