Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior.
Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior.
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DOI：
10.1038/mp.2017.213
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发表时间：
2018-10
影响因子：
11
通讯作者：
Sohal VS
中科院分区：
文献类型：
--
作者：
Brumback AC;Ellwood IT;Kjaerby C;Iafrati J;Robinson S;Lee AT;Patel T;Nagaraj S;Davatolhagh F;Sohal VS
功能成像和基因表达研究都暗示内侧前额叶皮层（mPFC），特别是深层投射神经元，作为自闭症病理学的潜在位点。在这里，我们探讨了特定的深层前额叶神经元如何有助于自闭症小鼠模型的异常生理和行为。首先，我们发现在三种病因学不同的模型中-子宫内丙戊酸（VPA）暴露，CNTNAP 2敲除和FMR 1敲除-第5层皮质下投射（SC）神经元始终表现出降低的输入电阻和动作电位放电。为了探索改变的SC神经元生理学如何影响行为，我们利用了在mPFC的深层中多巴胺D2受体（D2 Rs）主要由SC神经元表达的事实，并使用D2-Cre小鼠标记D2 R+神经元用于钙成像或光遗传学。我们发现，社会探索优先招聘mPFC D2 R+细胞，但这种招聘是衰减VPA暴露的小鼠。刺激mPFC D2 R+神经元会破坏正常的社会互动。相反，抑制这些细胞会增强暴露于VPA的小鼠的社交行为。重要的是，这种效应不能通过非特异性抑制VPA暴露小鼠的mPFC神经元或抑制野生型小鼠的D2 R+神经元来重现。这些发现表明，多种形式的自闭症可能会改变特定的深层前额叶神经元的生理功能，这些神经元投射到皮层下的目标。此外，一个高度重叠的群体-前额叶D2 R+神经元-在正常和异常的社会行为中起着重要作用，因此靶向这些细胞可以产生潜在的治疗效果。
Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models – in utero valproic acid (VPA) exposure, CNTNAP2 knockout, and FMR1 knockout – layer 5 subcortically-projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA-exposed mice, or by inhibiting D2R+ neurons in wildtype mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep-layer prefrontal neurons which project to subcortical targets. Furthermore, a highly overlapping population – prefrontal D2R+ neurons – plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects.