Pten haploinsufficiency disrupts scaling across brain areas during development in mice

Amy E Clipperton-Allen,Jacob Ellegood,Jason P Lerch,Ori S Cohen,Jenna Levy,Aya Zucca,Massimiliano Aceti,Damon T Page

doi:10.1038/s41398-019-0656-6

Abstract

Haploinsufficiency for PTEN is a cause of autism spectrum disorder and brain overgrowth; however, it is not known if PTEN mutations disrupt scaling across brain areas during development. To address this question, we used magnetic resonance imaging to analyze brains of male Pten haploinsufficient (Pten+/−) mice and wild-type littermates during early postnatal development and adulthood. Adult Pten+/− mice display a consistent pattern of abnormal scaling across brain areas, with white matter (WM) areas being particularly affected. This regional and WM enlargement recapitulates structural abnormalities found in individuals with PTEN haploinsufficiency and autism. Early postnatal Pten+/− mice do not display the same pattern, instead exhibiting greater variability across mice and brain regions than controls. This suggests that Pten haploinsufficiency may desynchronize growth across brain regions during early development before stabilizing by maturity. Pten+/− cortical cultures display increased proliferation of glial cell populations, indicating a potential substrate of WM enlargement, and provide a platform for testing candidate therapeutics. Pten haploinsufficiency dysregulates coordinated growth across brain regions during development. This results in abnormally scaled brain areas and associated behavioral deficits, potentially explaining the relationship between PTEN mutations and neurodevelopmental disorders.

Highlights

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder (1:59 children in USA1) characterized by deficits in social behavior and communication, and restricted, repetitive behavior and interests[2]
Absolute volume increases in gray matter (GM) (P7: 11.0%; P60: 17.7%; Fig. 1b, d), white matter (WM) (P7: 10.6%; P60: 20.6%; Fig. 1b, d), and almost all measured structures were found in Pten+/− mice at both ages
We found that Pten+/− cultures showed higher percentages of oligodendrocyte transcription factor 2 (Olig2)+ and Sex determining region Y-box 9 (Sox9)+ cells that were colabeled with BrdU (Olig2+BrdU+/Olig2+ and Sox9+BrdU+/Sox9+, respectively) at DIV12 (Fig. 4m–p)

Summary

Introduction

Autism spectrum disorder (ASD) is a common neurodevelopmental disorder (1:59 children in USA1) characterized by deficits in social behavior and communication, and restricted, repetitive behavior and interests[2]. 15–20% of the clinical ASD population show macrocephaly[3,4,5]. Of these, ~10–25%6–12 have mutations in the gene PTEN (Phosphatase and tensin homolog), which is causative of macrocephaly/autism syndrome (MIM #605309). PTEN mutations have been shown to induce macrocephaly and brain overgrowth, the pattern of enlargement at the level of individual brain areas during development has not been characterized. Individuals with PTEN mutations show brain enlargement and white matter (WM) abnormalities, some with changes in ventricular volume, vascular malformations, enlarged perivascular spaces, and/or gray matter (GM) heterotopia[13,14,15,16,17]. Individuals with ASD and PTEN mutations (PTEN-ASD) had considerably greater brain enlargement than those with ASD without a PTEN mutation (with or without macrocephaly) and healthy controls[14]. The increased WM volume, along with increased WM hypointensities (suggestive of increased myelination), in PTEN-ASD were related to observed deficits in IQ, processing speed, and working memory[14]

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Conclusion