Supplementary Material for: Sequence of Molecular Events during the Maturation of the Developing Mouse Prefrontal Cortex

Recent progress in psychiatric research has accumulated many mouse models relevant to developmental neuropsychiatric disorders using numerous genetic and environmental manipulations. Since the prefrontal cortex (PFC) is essential for cognitive functions whose impairments are central symptoms associated with the disorders in humans, it has become crucial to clarify altered developmental processes of PFC circuits in these mice. To that end, we aimed to understand a sequence of molecular events during normal mouse PFC development. Expression profiles for representative genes covering diverse biological processes showed that while there were little changes in genes for neuroreceptors and synaptic molecules during the postnatal period, there were dramatic increases in the expression of myelin-related genes and the parvalbumin gene, peaking at postnatal day (P)21 and P35, respectively. The timing of the peaks is different from that observed in the striatum. Furthermore, the evaluation of the circuitry maturation by measuring extracellular glutamate in the PFC revealed that sensitivity to an NMDA antagonist did not become an adult-like pattern till P56, suggesting that some of the maturation processes continue till P56. The trajectory of molecular events in PFC maturation described here should help us to characterize how the processes are affected in disease model mice, an important first step for translational research.

近年来，精神病学研究领域取得诸多进展，通过多种遗传与环境操控手段，已构建出大量与发育性神经精神疾病相关的小鼠模型。由于前额叶皮层（prefrontal cortex, PFC）是认知功能的关键调控脑区，而认知损伤正是人类此类疾病的核心临床症状，因此阐明此类模型小鼠前额叶皮层神经环路的发育异常机制已成为亟待突破的关键科学问题。为此，本研究旨在解析正常小鼠前额叶皮层发育过程中的一系列分子事件。对涵盖多种生物学过程的代表性基因开展表达谱分析后发现：小鼠出生后阶段，神经受体与突触分子相关基因的表达无显著变化，但髓鞘相关基因以及小白蛋白（parvalbumin）基因的表达量则显著上调，分别在出生后第21天（P21）与第35天（P35）达到峰值。上述两个峰值的出现时间与纹状体（striatum）中的观测结果存在显著差异。此外，通过检测前额叶皮层胞外谷氨酸水平评估神经环路成熟度的实验显示，小鼠直至出生后第56天（P56），其对N-甲基-D-天冬氨酸（NMDA）受体拮抗剂的敏感性才趋近成年个体水平，提示前额叶皮层的部分成熟过程可持续至P56阶段。本研究揭示的前额叶皮层成熟相关分子事件轨迹，将有助于解析疾病模型小鼠中该发育过程的异常改变，这也是转化研究的重要起步环节。