Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons.
Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons.
复制标题
DOI：
10.1038/mp.2015.222
复制
发表时间：
2016-07
影响因子：
11
通讯作者：
Kellendonk C
中科院分区：
文献类型：
--
作者：
Canetta S;Bolkan S;Padilla-Coreano N;Song LJ;Sahn R;Harrison NL;Gordon JA;Brown A;Kellendonk C
前额叶GABA能传递的异常，特别是在表达小清蛋白（PV）的快速尖峰中间神经元中，被假设为有助于多种精神疾病的病理生理学，包括精神分裂症，双相情感障碍，焦虑症和抑郁症。虽然在精神疾病的患者和动物模型中观察到了主要的组织学异常，但在动物模型中缺乏在特定中间神经元群体水平上的功能性神经传递异常的证据，并且难以在人类患者中建立。使用一个动物模型的精神疾病的危险因素，产前母体免疫激活（MIA），我们发现减少功能性GABA能传递内侧前额叶皮层（mPFC）的成年MIA后代。减少传输是选择性的表达PV的中间神经元，并没有观察到钙视黄蛋白表达的神经元。MIA后代的PV功能缺陷与焦虑样行为增加和注意力转移障碍有关，但不影响工作记忆。此外，mPFC PV中间神经元的细胞类型特异性光遗传学抑制足以损害注意力转移并增强焦虑水平。最后，我们发现，在体内mPFC γ振荡，这是支持PV中间神经元功能，与成年小鼠的焦虑程度呈线性相关，这种相关性被破坏在MIA后代。这些结果表明，PV中间神经元对母体免疫激活的选择性功能脆弱性，导致与精神分裂症和其他精神障碍高度相关的情感和认知症状。
Abnormalities in prefrontal GABAergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to maternal immune activation, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders.