PTEN mutations in autism spectrum disorder and congenital hydrocephalus: developmental pleiotropy and therapeutic targets. Issue 12 (December 2021)

• Record Type: Journal Article
• Authors: DeSpenza, Tyrone; Carlson, Marina; Panchagnula, Shreyas; Robert, Stephanie; Duy, Phan Q.; Mermin-Bunnell, Nell; Reeves, Benjamin C.; Kundishora, Adam; Elsamadicy, Aladine A.; Smith, Hannah; Ocken, Jack; Alper, Seth L.; Jin, Sheng Chih; Hoffman, Ellen J.; Kahle, Kristopher T.
• Is Part Of: Trends in neurosciences. Volume 44:Issue 12(2021)
• Page Start: 961
• Page End: 976
• Publication Date: 2021-12
• Subjects: neurodevelopmental disorders -- ventriculomegaly -- macrocephaly -- mTOR -- rapamycin; Neurology -- Periodicals; Neurophysiology -- Periodicals; Neurobiology -- Periodicals; 612.8
• DOI: 10.1016/j.tins.2021.08.007
• Languages: English
• ISSNs: 0166-2236

Abstract

Abstract : The lack of effective treatments for autism spectrum disorder (ASD) and congenital hydrocephalus (CH) reflects the limited understanding of the biology underlying these common neurodevelopmental disorders. Although ASD and CH have been extensively studied as independent entities, recent human genomic and preclinical animal studies have uncovered shared molecular pathophysiology. Here, we review and discuss phenotypic, genomic, and molecular similarities between ASD and CH, and identify the PTEN–PI3K–mTOR (phosphatase and tensin homolog–phosphoinositide 3-kinase–mammalian target of rapamycin) pathway as a common underlying mechanism that holds diagnostic, prognostic, and therapeutic promise for individuals with ASD and CH. Highlights: Structural brain abnormalities, such as enlargement of the brain's ventricles, occur at an increased frequency in individuals with autism spectrum disorder (ASD). Conversely, rates of ASD are increased in congenital hydrocephalus (CH) compared with the general population. These observations raise the question of whether the two disorders might share common neurodevelopmental mechanisms. Mutations in PTEN are associated with a range of neurodevelopmental disorders, including ASD and CH. Integrative genomics highlights PTEN–PI3K–mTOR as one potentially shared pathway between ASD and CH. Mouse models of PTEN loss of function exhibit macrocephaly, social deficits, seizures, synaptic alterations, myelination defects, and enlarged brain ventricles. Preclinical studies in mouse models suggest that targeting the mTOR pathway can reverse structural and behavioral abnormalities associated with PTEN loss of function. The PTEN–PI3K–mTOR pathway may represent a potential pharmacological target for further investigation in ASD and CH.