Author:
DeSpenza Tyrone,Kiziltug Emre,Allington Garrett,Barson Daniel G.,O’Connor David,Robert Stephanie M.,Mekbib Kedous Y.,Nanda Pranav,Greenberg Ana,Singh Amrita,Duy Phan Q.,Mandino Francesca,Zhao Shujuan,Lynn Anna,Reeves Benjamin C.,Marlier Arnaud,Getz Stephanie A.,Nelson-Williams Carol,Shimelis Hermela,Walsh Lauren K.,Zhang Jinhui,Wang Wei,OuYang Annaliese,Smith Hannah,Butler William,Carter Bob S.,Deniz Engin,Lake Evelyn M. R.,Constable Todd,Gûnel Murat,Lifton Richard P.,Alper Seth L.,Chih Jin Sheng,Crair Michael C.,Moreno-De-Luca Andres,Luikart Bryan W.,Kahle Kristopher T.
Abstract
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.
Publisher
Cold Spring Harbor Laboratory