Brain transcriptome analysis of Slc6a20a heterozygous and homozygous mutant mice

SLC6A20A is a proline and glycine transporter known to regulate glycine homeostasis and NMDA receptor (NMDAR) function in the brain. A previous study on Slc6a20a-haploinsufficient mice reported increases in ambient glycine levels and NMDA receptor-mediated synaptic transmission in the brain, but whether Slc6a20a deficiency leads to disease-related behavioral deficits in mice remains unknown. Here, we report that Slc6a20a heterozygous and homozygous mutant mice display gene dosage-dependent behavioral phenotypes in locomotor, repetitive behavioral, and fear memory domains. In addition, Slc6a20a heterozygous and homozygous mutant brains showed transcriptomic changes in synapse, ribosome, and mitochondria-related genes as well as autism, epilepsy, and neuron-related genes. These results suggest that Slc6a20a deletion leads to gene dosage-dependent behavioral deficits in mice and transcriptomic changes in genes associated with synapse, ribosome, mitochondria, ASD, epilepsy, and neurons Whole-brain transcriptome analysis of Slc6a20a heterozygous and homozygous mutant mice age of P120SLC6A20A是一种脯氨酸与甘氨酸转运蛋白，已知可调控大脑内的甘氨酸稳态以及N-甲基-D-天冬氨酸受体（NMDA receptor，NMDAR）的功能。既往一项针对Slc6a20a单倍剂量不足小鼠的研究显示，其大脑内的细胞外甘氨酸水平与NMDA受体介导的突触传递均有所升高，但Slc6a20a缺陷是否会导致小鼠出现疾病相关的行为缺陷仍未明确。本研究发现，Slc6a20a杂合与纯合突变小鼠在运动行为、重复刻板行为与恐惧记忆相关维度中均表现出基因剂量依赖性的行为表型。此外，Slc6a20a杂合及纯合突变小鼠的大脑在突触、核糖体、线粒体相关基因以及自闭症（Autism）、癫痫、神经元相关基因中均出现了转录组表达变化。上述结果表明，Slc6a20a缺失会导致小鼠出现基因剂量依赖性的行为缺陷，并引发与突触、核糖体、线粒体、自闭症谱系障碍（ASD）、癫痫及神经元相关基因的转录组表达变化。本研究对出生后120日龄（P120）的Slc6a20a杂合与纯合突变小鼠开展了全脑转录组分析。