Althammer Ferdinand, Wimmer Moritz Claudius, Krabichler Quirin, Küppers Stephanie, Schimmer Jonas, Fröhlich Henning, Dötsch Laura, Gruber Tim, Wunsch Selina, Schubert Tim, Kirchner Matthew K, Stern Javier E, Charlet Alexandre, Grinevich Valery, Schaaf Christian P
Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
Department of Neuropeptide Research in Psychiatry, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany.
J Neuroendocrinol. 2022 Dec;34(12):e13217. doi: 10.1111/jne.13217. Epub 2022 Dec 1.
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia, obesity, developmental delay and intellectual disability. Studies suggest dysfunctional signaling of the neuropeptide oxytocin as one of the key mechanisms in PWS, and administration of oxytocin via intranasal or systemic routes yielded promising results in both humans and mouse models. However, a detailed assessment of the oxytocin system in mouse models of PWS such as the Magel2-deficient Magel2 mouse, is lacking. In the present study, we performed an automated counting of oxytocin cells in the entire paraventricular nucleus of the hypothalamus of Magel2 and wild-type control mice and found a significant reduction in the caudal part, which represents the parvocellular subdivision. In addition, based on the recent discovery that some astrocytes express the oxytocin receptor (OTR), we performed detailed analysis of astrocyte numbers and morphology in various brain regions, and assessed expression levels of the astrocyte marker glial fibrillary acidic protein, which was significantly decreased in the hypothalamus, but not other brain regions in Magel2 mice. Finally, we analyzed the number of OTR-expressing astrocytes in various brain regions and found a significant reduction in the nucleus accumbens of Magel2 mice, as well as a sex-specific difference in the lateral septum. This study suggests a role for caudal paraventricular nucleus oxytocin neurons as well as OTR-expressing astrocytes in a mouse model of PWS, provides novel information about sex-specific expression of astrocytic OTRs, and presents several new brain regions containing OTR-expressing astrocytes in the mouse brain.
普拉德-威利综合征（PWS）是一种神经发育障碍，其特征为食欲亢进、肥胖、发育迟缓及智力残疾。研究表明，神经肽催产素信号功能失调是PWS的关键机制之一，经鼻内或全身途径给予催产素在人类和小鼠模型中均产生了有前景的结果。然而，缺乏对PWS小鼠模型（如Magel2基因缺陷的Magel2小鼠）中催产素系统的详细评估。在本研究中，我们对Magel2小鼠和野生型对照小鼠下丘脑室旁核全核的催产素细胞进行了自动计数，发现代表小细胞亚群的尾部显著减少。此外，基于最近发现一些星形胶质细胞表达催产素受体（OTR），我们对不同脑区的星形胶质细胞数量和形态进行了详细分析，并评估了星形胶质细胞标志物胶质纤维酸性蛋白的表达水平，其在下丘脑显著降低，但在Magel2小鼠的其他脑区未降低。最后，我们分析了不同脑区表达OTR的星形胶质细胞数量，发现Magel2小鼠伏隔核中的数量显著减少，以及外侧隔区存在性别特异性差异。本研究表明，在PWS小鼠模型中，室旁核尾部催产素神经元以及表达OTR的星形胶质细胞发挥了作用，提供了关于星形胶质细胞OTR性别特异性表达的新信息，并揭示了小鼠脑中几个含有表达OTR星形胶质细胞的新脑区。
