PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors

Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (ventriculomegaly) is a defining feature of congenital hydrocephalus (CH) and an underrecognized concomitant of autism. Here, we show that de novo mutations in the autism risk gene, PTEN, are among the most frequent monogenic causes of CH and primary ventriculomegaly. Mouse Pten-mutant ventriculomegaly results from aqueductal stenosis due to hyperproliferation of periventricular Nkx2.1+ neuroprogenitor cells (NPCs) and increased CSF production from hyperplastic choroid plexus. Pten-mutant ventriculomegalic cortices exhibit network dysfunction from increased activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or post-natal everolimus treatment corrects ventriculomegaly, rescues cortical deficits, and increases survival by antagonizing mTORC1-dependent Nkx2.1+ NPC pathology. Thus, PTEN mutations concurrently alter CSF dynamics and cortical networks by dysregulating Nkx2.1+ NPCs. These results implicate a non-surgical treatment for CH, demonstrate a genetic association of ventriculomegaly and ASD, and help explain neurodevelopmental phenotypes refractory to CSF shunting in select CH patients. Examine the knockout effect of PTEN on choroid plexus, subventricular zone and cortex脑脊液（cerebrospinal fluid, CSF）充盈的脑室扩大（ventriculomegaly）是先天性脑积水（congenital hydrocephalus, CH）的标志性病理特征，同时也是未被充分认知的自闭症伴随表型。本研究证实，自闭症风险基因PTEN的新发突变，是先天性脑积水及原发性脑室扩大最常见的单基因病因之一。 Pten突变小鼠的脑室扩大表型，源于中脑导水管狭窄，其具体机制包括脑室周围Nkx2.1阳性神经前体细胞（neuroprogenitor cells, NPCs）过度增殖，以及增生性脉络丛的脑脊液生成量增加。 Pten突变致脑室扩大的小鼠皮层，因Nkx2.1阳性神经前体细胞来源的抑制性中间神经元活性增强，出现神经网络功能障碍。 敲除Raptor基因或产后给予依维莫司治疗，可通过拮抗mTORC1依赖型Nkx2.1阳性神经前体细胞的病理变化，纠正脑室扩大、挽救皮层功能缺陷并提高小鼠生存率。 综上，PTEN突变通过失调Nkx2.1阳性神经前体细胞，同时改变脑脊液动力学与皮层神经网络。本研究结果为先天性脑积水提供了非手术治疗方案，证实了脑室扩大与自闭症的遗传关联，并有助于解释特定先天性脑积水患者中，对脑脊液分流术耐受的神经发育表型。本研究同时考察了PTEN对脉络丛、室下区及大脑皮层的敲除效应。