1 Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
2 Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Mol Imaging. 2019 Jan-Dec;18:1536012118821034. doi: 10.1177/1536012118821034.
MET, the gene encoding the tyrosine kinase receptor for hepatocyte growth factor, is a susceptibility gene for autism spectrum disorder (ASD). Genetically altered mice with a kinase-inactive Met offer a potential model for understanding neural circuit organization changes in autism. Here, we focus on the somatosensory thalamocortical circuitry because distinct somatosensory sensitivity phenotypes accompany ASD, and this system plays a major role in sensorimotor and social behaviors in mice. We employed resting-state functional magnetic resonance imaging and in vivo high-resolution proton MR spectroscopy to examine neuronal connectivity and neurotransmission of wild-type, heterozygous Met-Emx1, and fully inactive homozygous Met-Emx1 mice. Met-Emx1 brains showed impaired maturation of large-scale somatosensory network connectivity when compared with wild-type controls. Significant sex × genotype interaction in both network features and glutamate/gamma-aminobutyric acid (GABA) balance was observed. Female Met-Emx1 brains showed significant connectivity and glutamate/GABA balance changes in the somatosensory thalamocortical system when compared with wild-type brains. The glutamate/GABA ratio in the thalamus was correlated with the connectivity between the somatosensory cortex and the thalamus in heterozygous Met-Emx1 female brains. The findings support the hypothesis that aberrant functioning of the somatosensory thalamocortical system is at the core of the conspicuous somatosensory behavioral phenotypes observed in Met-Emx1 mice.
MET 基因编码肝细胞生长因子的酪氨酸激酶受体，是自闭症谱系障碍（ASD）的易感基因。具有激酶失活 Met 的基因改变小鼠为理解自闭症中的神经回路组织变化提供了一个潜在模型。在这里，我们专注于躯体感觉丘脑皮质回路，因为 ASD 伴随着明显的躯体感觉敏感性表型，并且该系统在小鼠的感觉运动和社会行为中起主要作用。我们采用静息态功能磁共振成像和体内高分辨率质子磁共振波谱来检查野生型、杂合 Met-Emx1 和完全失活的纯合 Met-Emx1 小鼠的神经元连接和神经传递。与野生型对照相比，Met-Emx1 大脑显示出大规模躯体感觉网络连接的成熟受损。在网络特征和谷氨酸/γ-氨基丁酸（GABA）平衡方面观察到显著的性别×基因型相互作用。与野生型大脑相比，雌性 Met-Emx1 大脑在躯体感觉丘脑皮质系统中显示出显著的连接和谷氨酸/GABA 平衡变化。丘脑中的谷氨酸/GABA 比值与杂合 Met-Emx1 雌性大脑中感觉皮层和丘脑之间的连接呈正相关。这些发现支持这样的假设，即躯体感觉丘脑皮质系统的异常功能是 Met-Emx1 小鼠中明显的躯体感觉行为表型的核心。
