# The Impact of PTEN Signaling on Neuronal Form and Function

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2020 · $450,559

## Abstract

ABSTRACT
 PTEN is a phosphatidylinositol phosphatase that antagonizes signaling downstream of growth factor
receptors. Mutations in PTEN have repeatedly been identified in patients with autism spectrum disorder (ASD)
and macrocephaly. Further, experimental deletion of Pten in the mouse brain causes macrocephaly and
deficits in social behavior, suggesting a causative role in the development of ASD. In neurons, Pten knockout
results in aberrant growth and increased excitatory synapse function. Thus, studying Pten fits with our long-
term goal of understanding how synaptic connectivity and activity contribute to cognitive and emotional
processes. My central hypothesis is that Pten dysfunction causes aberrant neuronal growth and
excitability leading to altered synaptic circuit formation during development.
 Guided by this hypothesis, the specific aims of this proposal will strengthen our understanding of the
molecular and neurophysiological basis of ASD. There is a lack of pharmacological therapies for ASDs
because we are just beginning to identify the molecular mechanisms underlying these disorders. We have
defined a set of robust and reproducible cellular phenotypes elicited by Pten knockout in developing neurons.
Understanding the molecular mechanisms underlying cellular phenotypes could lead to new treatments for
ASDs. Our first aim will test the hypothesis that cellular phenotypes are caused by deregulation of
translation and cytoskeletal organization to alter the developmental elaboration of neurons.
 Defining cell-autonomous changes in neuronal development is a first step into understanding the
emergent impact on network formation and function. Our second aim will test our central hypothesis by
determining whether Pten knockout results in similar cellular phenotypes across neuronal types and
contexts. Different genetic models of ASDs display disparate cellular changes. Some models display
synaptic hyperconnectivity while others display hypoconnecectivity and there is variability in
excitation/inhibition ratios. Activity-dependent sculpting of synaptic connectivity during development
fundamentally shapes network activity allowing for appropriate responses to our environment. A common
feature shared by models of ASD may be pathological activity-dependent sculpting of synaptic connectivity
during development. For the third aim, we will test the hypothesis that Pten dysfunction alters the
activity-dependent sculpting of neuronal connectivity during development.
 This proposal will use innovative genetic approaches to manipulate gene expression and control
neuronal activity in vivo. We will test the consequences of these genetic manipulations through detailed
neuronal morphological and electrophysiological analyses. The broad goal of this research is to define the
molecular basis of how Pten dysfunction contributes to aberrant neuronal development and network function.

## Key facts

- **NIH application ID:** 9888423
- **Project number:** 5R01MH097949-09
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** BRYAN W LUIKART
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,559
- **Award type:** 5
- **Project period:** 2012-07-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9888423

## Citation

> US National Institutes of Health, RePORTER application 9888423, The Impact of PTEN Signaling on Neuronal Form and Function (5R01MH097949-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9888423. Licensed CC0.

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