SUMMARYExpansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles (ventriculomegaly) is the quintessential feature of congenital hydrocephalus (CH) but also seen in autism spectrum disorder (ASD) and several neuropsychiatric diseases.PTENis frequently mutated in ASD; here, we showPTENis abona fiderisk gene for the development of ventriculomegaly, including neurosurgically-treated CH.Pten-mutant hydrocephalus is associated with aqueductal stenosis due to the hyperproliferation of periventricularNkx2.1+neural precursors (NPCs) and CSF hypersecretion from inflammation-dependent choroid plexus hyperplasia. The hydrocephalicPten-mutant cortex exhibits ASD-like network dysfunction due to impaired activity ofNkx2.1+NPC-derived inhibitory interneurons.Raptordeletion or post-natal Everolimus corrects ventriculomegaly, rescues cortical deficits, and increases survival by antagonizing mTORC1-dependentNkx2.1+cell pathology. These results implicate a dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of NPCs and their interneuron descendants. These data identify a non-surgical treatment target for hydrocephalus and have implications for other developmental brain disorders.HIGHLIGHTSPTEN de novomutations are associated with cerebral ventriculomegaly in autism spectrum disorder (ASD) and congenital hydrocephalus (CH).Pten-mutant hydrocephalus is associated with aqueductal stenosis due to the hyperproliferation of medial ganglionic eminenceNkx2.1+neural precursors and CSF hypersecretion from inflammation-induced choroid plexus hyperplasia.The hydrocephalicPten-mutant cortex exhibits ASD-like network dysfunction due to impaired activity ofNkx2.1+NPC-derived inhibitory interneurons.mTORC1 inhibition viaRaptordeletion or early post-natal treatment with rapamycin or everolimus increases survival and amelioratesPten-mutant ventriculomegaly and cortical pathology.
