Center for Molecular Morphology, Section for Stereology and Microscopy, Center for Stochastic Geometry and Advanced Bioimaging, Department of Clinical Medicine, Aarhus University, 8000 Aarhus, Denmark.
Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark.
Cereb Cortex. 2021 Feb 5;31(3):1609-1621. doi: 10.1093/cercor/bhaa313.
The 15q13.3 deletion is associated with multiple neurodevelopmental disorders including epilepsy, schizophrenia, and autism. The Df(h15q13)/+ mouse model was recently generated that recapitulates several phenotypic features of the human 15q13.3 deletion syndrome (DS). However, the biological substrates underlying these phenotypes in Df(h15q13)/+ mice have not yet been fully characterized. RNA sequencing followed by real-time quantitative PCR, western blotting, liquid chromatography-mass spectrometry, and stereological analysis were employed to dissect the molecular, structural, and neurochemical phenotypes of the medial prefrontal cortex (mPFC) circuits in Df(h15q13)/+ mouse model. Transcriptomic profiling revealed enrichment for astrocyte-specific genes among differentially expressed genes, translated by a decrease in the number of glial fibrillary acidic protein positive cells in mPFC of Df(h15q13)/+ mice compared with wild-type mice. mPFC in Df(h15q13)/+ mice also showed a deficit of the inhibitory presynaptic marker GAD65, in addition to a reduction in dendritic arborization and spine density of pyramidal neurons from layers II/III. mPFC levels of GABA and glutamate neurotransmitters were not different between genotypes. Our results suggest that the 15q13.3 deletion modulates nonneuronal circuits in mPFC and confers molecular and morphometric alterations in the inhibitory and excitatory neurocircuits, respectively. These alterations potentially contribute to the phenotypes accompanied with the 15q13.3DS.
15q13.3 缺失与多种神经发育障碍有关，包括癫痫、精神分裂症和自闭症。最近生成了 Df(h15q13)/+ 小鼠模型，该模型重现了人类 15q13.3 缺失综合征 (DS) 的几种表型特征。然而，Df(h15q13)/+ 小鼠中这些表型的生物学基础尚未得到充分表征。采用 RNA 测序、实时定量 PCR、western blot、液相色谱-质谱联用和立体学分析来剖析 Df(h15q13)/+ 小鼠模型中内侧前额叶皮层 (mPFC) 回路的分子、结构和神经化学表型。转录组谱分析显示，差异表达基因中富含星形胶质细胞特异性基因，与野生型小鼠相比，Df(h15q13)/+ 小鼠 mPFC 中的胶质纤维酸性蛋白阳性细胞数量减少。Df(h15q13)/+ 小鼠的 mPFC 还显示抑制性突触标记物 GAD65 减少，除了 II/III 层的锥体神经元树突分支和棘密度减少。两种基因型之间 mPFC 的 GABA 和谷氨酸神经递质水平没有差异。我们的结果表明，15q13.3 缺失调节 mPFC 中的非神经元回路，并分别在抑制性和兴奋性神经回路中赋予分子和形态计量改变。这些改变可能有助于 15q13.3DS 伴随的表型。
