Cortical Foxp2 Supports Behavioral Flexibility and Developmental Dopamine D1 Receptor Expression
Cortical Foxp2 Supports Behavioral Flexibility and Developmental Dopamine D1 Receptor Expression
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DOI：
10.1093/cercor/bhz209
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发表时间：
2020-03-01
期刊：
影响因子：
3.7
通讯作者：
Konopka, Genevieve
中科院分区：
文献类型：
--
作者：
Co, Marissa;Hickey, Stephanie L.;Konopka, Genevieve
遗传研究已经将FOXP2变异与言语和语言障碍以及涉及皮层病理的其他神经发育障碍（NDD）相关联。在这个大脑区域，FoxP2从发育到成年都有表达，但对其下游分子和行为功能知之甚少。在这里，我们描述了皮质特异性Foxp2条件性敲除小鼠的特征，并发现了逆转学习的主要缺陷，这是一种行为灵活性。相比之下，他们表现出正常的活动水平，焦虑，发声，除了新生儿呼叫响度略有下降。这些行为表型伴随着皮质多巴胺D1受体（D1R）的表达在新生儿和成人阶段下降，而一般的皮质发育不受影响。最后，使用单细胞转录组学，我们确定了至少五个兴奋性和三个抑制性D1R表达细胞类型在新生儿额叶皮层，我们发现D1R细胞类型组成和基因表达的变化后，皮质Foxp2删除。引人注目的是，这些变化包括上层神经元和中间神经元的非细胞自主变化。总之，这些数据支持Foxp2在多巴胺调制的皮层回路和与NDD相关的行为的发展中的作用。
Genetic studies have associated FOXP2 variation with speech and language disorders and other neurodevelopmental disorders (NDDs) involving pathology of the cortex. In this brain region, FoxP2 is expressed from development into adulthood, but little is known about its downstream molecular and behavioral functions. Here, we characterized cortex-specific Foxp2 conditional knockout mice and found a major deficit in reversal learning, a form of behavioral flexibility. In contrast, they showed normal activity levels, anxiety, and vocalizations, save for a slight decrease in neonatal call loudness. These behavioral phenotypes were accompanied by decreased cortical dopamine D1 receptor (D1R) expression at neonatal and adult stages, while general cortical development remained unaffected. Finally, using single-cell transcriptomics, we identified at least five excitatory and three inhibitory D1R-expressing cell types in neonatal frontal cortex, and we found changes in D1R cell type composition and gene expression upon cortical Foxp2 deletion. Strikingly, these alterations included non-cell-autonomous changes in upper layer neurons and interneurons. Together, these data support a role for Foxp2 in the development of dopamine-modulated cortical circuits and behaviors relevant to NDDs.