# Delineating contributions of PI3K signaling to neurodevelopmental consequences of Pten haploinsufficiency

> **NIH NIH R21** · SCRIPPS FLORIDA · 2021 · $182,140

## Abstract

Project Summary/Abstract
Autism spectrum disorder (ASD) is a remarkably heterogeneous collection of conditions that converge on the
symptoms of social and communication difficulties, together with restricted interests and repetitive behavior.
Underlying this heterogeneity is likely a variety of etiologies. Thus, it has become clear in recent years that a
“one-size-fits-all” approach to treating ASD is not sufficient. Rather, stratifying individuals based on particular
risk factors and symptoms is increasingly being explored as a way to develop targeted personalized treatments
for ASD. One risk factor that is receiving significant attention in this context is mutations in the gene PTEN,
which encodes a key regulator of growth in the developing body and brain. Germline heterozygous mutations
in this gene, which generally reduce levels of PTEN protein, are common in individuals with ASD and
macrocephaly (overgrowth of the head and brain). Our laboratory has shown that mice carrying equivalent
mutations in Pten display both brain overgrowth and social behavioral deficits, establishing that a reduction in
Pten protein level is sufficient to cause ASD-relevant symptoms in an animal model. Pten encodes a
phosphatase that acts as a negative regulator of the enzyme phosphoinositide 3-kinase (PI3K), and
dysregulation of the PI3K-Akt-mTOR pathway has been linked with neurodevelopmental pathobiology across a
variety of preclinical models of ASD. Much attention has been given to inhibition of mTOR, and in particular
mTOR complex 1 (mTORC1), as a strategy for treating the neurodevelopmental phenotypes arising from
mutations in PTEN and other regulators of the PI3K-Akt-mTOR pathway. In contrast, the therapeutic potential
of PI3K inhibition is underexplored, and has not been tested in validated in vivo preclinical models of Pten
haploinsufficiency. This project aims to address this problem and to delineate the contributions of PI3K
signaling to neurodevelopmental phenotypes resulting from Pten haploinsufficiency. Our overarching
hypothesis is that treatment of Pten+/- mice via PI3K inhibition during development will rescue ASD-relevant
phenotypes by normalizing downstream signaling. The two aims of this proposal will test this hypothesis
through genetic suppression of PI3K in Pik3ca; Pten compound mutant mice (Aim 1) and through treating Pten
haploinsufficient mice with a pharmacological PI3K inhibitor at distinct time windows during development to
identify a critical period for treatment (Aim 2). For both aims, robust and reproducible ASD-relevant
neuroanatomical and behavioral phenotypes in Pten haploinsufficient mice will be used as readouts.
Key outcomes of this work will include preclinical testing of PI3K inhibition as a potential therapeutic approach
to correct the neurodevelopmental consequences of PTEN mutations and the identification of a critical period
when treatment may lead to a suppression of ASD-relevant symptoms.

## Key facts

- **NIH application ID:** 10371825
- **Project number:** 1R21NS121951-01A1
- **Recipient organization:** SCRIPPS FLORIDA
- **Principal Investigator:** Damon Theron Page
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $182,140
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-04-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371825

## Citation

> US National Institutes of Health, RePORTER application 10371825, Delineating contributions of PI3K signaling to neurodevelopmental consequences of Pten haploinsufficiency (1R21NS121951-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10371825. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*