# The Impact of Pten Signaling on Neuronal Form and Function

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2022 · $682,112

## Abstract

Abstract
 PTEN is a phosphatidylinositol phosphatase that antagonizes signaling downstream of growth factor
receptors. Mutations in PTEN have 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 synaptic function. Thus, studying Pten fits with our long-term goal of
understanding how synaptic connectivity and activity contribute to cognitive and emotional functions. My central
hypothesis is that PTEN dysfunction causes aberrant neuronal growth 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. Manipulation of Pten in vivo presents a unique opportunity to
examine the neurophysiological basis of ASD in a model organism. Our first aim will test our central
hypothesis by determining the downstream signaling intermediates necessary for neuronal growth,
synapse formation, and increased excitability after Pten knockout. We have discovered that cytoskeletal
polymerization rate is increased in dendritic growth cones of neurons lacking Pten. We hypothesize that the
change in polymerization rate is not dependent on mTORC1 or protein synthesis and therefore represents a
parallel molecular pathway that could be targeted for treatment. Understanding the molecular mechanisms
underlying these cellular phenotypes could lead to new treatments for ASDs. Our second aim will define how
PTEN dependent cytoskeletal polymerization contributes to neuronal growth and synapse function and
test if this is mTORC2 dependent. A gap in our understanding of neuronal cell biology exists because signaling
downstream of Pten has been largely defined in immortalized cell lines. Thus, we do not know the requirements
for specific signaling intermediates regulating translation and cytoskeletal remodeling in specialized processes
such as dendritic branching, filopodial growth, and synapse formation. I hypothesize that PTEN function must
be regulated in distinct subcellular compartments to regulate soma migration and growth versus dendritic growth
and synapse formation. For the third aim, we will test subcellular localization of PTEN necessary to
regulate neuronal growth, synapse formation, and synapse function.
 This proposal will use innovative genetic approaches to both knockout endogenous mouse genes and
replace them with mutated forms in vivo. The strategy of gene knockout and molecular substitution will allow us
to test specific mechanisms regulating neuronal development and function. The broad goal of this research is
to understand the molecular basis of neuronal dendritic arborization facilitating synaptic contact and function.

## Key facts

- **NIH application ID:** 10444092
- **Project number:** 2R01MH097949-11
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** BRYAN W LUIKART
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $682,112
- **Award type:** 2
- **Project period:** 2012-07-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444092

## Citation

> US National Institutes of Health, RePORTER application 10444092, The Impact of Pten Signaling on Neuronal Form and Function (2R01MH097949-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10444092. Licensed CC0.

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