Cytoplasmic-predominant Pten increases microglial activation and synaptic pruning in a murine model with autism-like phenotype.,Molecular Psychiatry

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Cytoplasmic-predominant Pten increases microglial activation and synaptic pruning in a murine model with autism-like phenotype.
Molecular Psychiatry ( IF 9.6 ) Pub Date : 2020-02-13 , DOI: 10.1038/s41380-020-0681-0
Nicholas Sarn _{1,

2} , Ritika Jaini _{1,

3,

4} , Stetson Thacker _{1,

4} , Hyunpil Lee ₁ , Ranjan Dutta _{4,

5} , Charis Eng _{1,

2,

3,

4}

Affiliation

Germline mutations in PTEN account for ~10% of cases of autism spectrum disorder (ASD) with coincident macrocephaly. To explore the importance of nuclear PTEN in the development of ASD and macrocephaly, we previously generated a mouse model with predominantly cytoplasmic localization of Pten (Ptenm3m4/m3m4).Cytoplasmic predominant Pten localization results in a phenotype of extreme macrocephaly and autistic-like traits. Transcriptomic analysis of the Ptenm3m4/m3m4 cortex found upregulated gene pathways related to myeloid cell activation, myeloid cell migration, and phagocytosis. These transcriptomic findings were used to direct in vitro assays on Pten wild-type and Ptenm3m4/m3m4 microglia. We found increased Iba1 and C1q expression with enhanced phagocytic capacity in Ptenm3m4/m3m4 microglia, indicating microglial activation. Moreover, through a series of neuron-microglia co-culture experiments, we found Ptenm3m4/m3m4 microglia are more efficient at synaptic pruning compared with wild-type controls. In addition, we found evidence for neuron-microglia cross-talk, where Ptenm3m4/m3m4 neurons elicit enhanced pruning from innately activated microglia. Subsequent in vivo studies validated our in vitro findings. We observed a concurrent decline in the expression of Pten and synaptic markers in the Ptenm3m4/m3m4 cortex. At ~3 weeks of age, with a 50% drop in Pten expression compared with wild-type levels, we observed enhanced activation of microglia in the Ptenm3m4/m3m4 brain. Collectively, our data provide evidence that dysregulated Pten in microglia has an etiological role in microglial activation, phagocytosis, and synaptic pruning, creating avenues for future studies on the importance of PTEN in maintaining microglia homeostasis.

中文翻译：

在具有自闭症样表型的小鼠模型中，以细胞质为主的 Pten 增加了小胶质细胞的激活和突触修剪。

PTEN 中的种系突变占自闭症谱系障碍 (ASD) 病例的约 10%，同时伴有大头畸形。为了探索核 PTEN 在 ASD 和大头畸形发展中的重要性，我们之前生成了一个 Pten 主要在细胞质定位 (Ptenm3m4/m3m4) 的小鼠模型。细胞质主要 Pten 定位导致极端大头畸形和自闭症样特征的表型。Ptenm3m4/m3m4 皮质的转录组学分析发现与骨髓细胞活化、骨髓细胞迁移和吞噬作用相关的上调基因通路。这些转录组学发现用于指导 Pten 野生型和 Ptenm3m4/m3m4 小胶质细胞的体外测定。我们发现 Ptenm3m4/m3m4 小胶质细胞中 Iba1 和 C1q 表达增加，吞噬能力增强，表明小胶质细胞活化。而且，通过一系列神经元-小胶质细胞共培养实验，我们发现与野生型对照相比，Ptenm3m4/m3m4 小胶质细胞在突触修剪方面更有效。此外，我们发现了神经元-小胶质细胞串扰的证据，其中 Ptenm3m4/m3m4 神经元引发了先天激活的小胶质细胞的增强修剪。随后的体内研究验证了我们的体外研究结果。我们观察到 Ptenm3m4/m3m4 皮质中 Pten 和突触标记的表达同时下降。在约 3 周龄时，与野生型水平相比，Pten 表达下降 50%，我们观察到 Ptenm3m4/m3m4 大脑中小胶质细胞的激活增强。总的来说，我们的数据提供的证据表明，小胶质细胞中 Pten 失调在小胶质细胞激活、吞噬作用和突触修剪中具有病因学作用，

更新日期：2020-02-13

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