OBJECTIVE In schizophrenia, impaired working memory is associated with transcriptome alterations in layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC). Distinct subtypes of L3PNs that send axonal projections to the DLPFC in the opposite hemisphere (callosal projection [CP] neurons) or the parietal cortex in the same hemisphere (ipsilateral projection [IP] neurons) play critical roles in working memory. However, how the transcriptomes of these L3PN subtypes might shift during late postnatal development when working memory impairments emerge in individuals later diagnosed with schizophrenia is not known. The aim of this study was to characterize and compare the transcriptome profiles of CP and IP L3PNs across developmental transitions from prepuberty to adulthood in macaque monkeys. METHODS The authors used retrograde labeling to identify CP and IP L3PNs in the DLPFC of prepubertal, postpubertal, and adult macaque monkeys, and used laser microdissection to capture these neurons for RNA sequencing. RESULTS At all three ages, CP and IP L3PNs had distinct transcriptomes, with the number of genes differentially expressed between neuronal subtypes increasing with age. For IP L3PNs, age-related shifts in gene expression were most prominent between prepubertal and postpubertal animals, whereas for CP L3PNs such shifts were most prominent between postpubertal and adult animals. CONCLUSIONS These findings demonstrate the presence of cell type-specific profiles and developmental trajectories of the transcriptomes of PPC-projecting IP and DLPFC-projecting CP L3PNs in monkey DLPFC. The evidence that IP L3PNs reach a mature transcriptome earlier than CP L3PNs suggests that these two subtypes differentially contribute to the maturation of working memory performance across late postnatal development and that they may be differentially vulnerable to the disease process of schizophrenia at specific stages of postnatal development.

中文翻译：

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灵长类动物前额叶第 3 层锥体神经元转录组的细胞类型特异性谱和发育轨迹：对精神分裂症的影响。


目的 在精神分裂症中，工作记忆受损与背外侧前额叶皮层 （DLPFC） 第 3 层锥体神经元 （L3PNs） 的转录组改变有关。将轴突投射发送到对半球（胼胝体投射 [CP] 神经元）或同一半球顶叶皮层（同侧投射 [IP] 神经元）的不同 L3PN 亚型在工作记忆中起着关键作用。然而，当后来诊断为精神分裂症的个体出现工作记忆障碍时，这些 L3PN 亚型的转录组在出生后晚期如何变化尚不清楚。本研究的目的是表征和比较猕猴从青春期前到成年发育过渡中 CP 和 IP L3PNs 的转录组谱。方法 作者使用逆行标记鉴定青春期前、青春期后和成年猕猴 DLPFC 中的 CP 和 IP L3PNs，并使用激光显微切割捕获这些神经元进行 RNA 测序。结果 在所有三个年龄，CP 和 IP L3PNs 具有不同的转录组，神经元亚型间差异表达的基因数量随着年龄的增长而增加。对于 IP L3PNs，与年龄相关的基因表达变化在青春期前和青春期后动物中最为明显，而对于 CP L3PNs，这种变化在青春期后和成年动物之间最为明显。结论 这些发现证明了猴 DLPFC 中存在 PPC 投射 IP 和 DLPFC 投射 CP L3PNs 转录组的细胞类型特异性谱和发育轨迹。 IP L3PNs比CP L3PNs更早达到成熟转录组的证据表明，这两种亚型在出生后发育后期对工作记忆表现的成熟有差异的贡献，并且它们在出生后发育的特定阶段可能对精神分裂症的疾病过程具有差异性的脆弱性。