# Age-Dependent Dysfunction of GABAergic Neurotransmission Due to Autism-Associated mTOR Pathway Activation

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $393,229

## Abstract

Project Summary/Abstract
 Autism spectrum disorder (ASD) is a significant cause of morbidity and loss of developmental
potential in children. An increasing number of genetic and environmental factors are being identified that
contribute to ASD. Two major cellular pathways that have been implicated in both genetic and
environmental causes of ASD involve mTOR signaling and GABAergic neurotransmission. In this project,
we propose to investigate a mechanistic link between these pathways that may explain both the age
dependence and male sex predominance of core ASD symptoms and comorbidities.
 In this project, we propose to test the hypothesis that autism-associated mTOR pathway activation
causes differential dysregulation of GABAergic neurotransmission in the immature versus the mature
brain. Further, we hypothesize that this dysregulation will be more pronounced in males than in females.
We will examine our hypotheses through pursuit of the following Specific Aims. Specific Aim 1: To test
the hypothesis that mTOR pathway activation accelerates the development of hyperpolarizing GABAA
receptor function in the immature brain. Cultured cortical neurons and transgenic mice with mTOR
pathway activation, either via heterozygous loss of the Pten or Tsc2 genes or via expression of a
constitutively active form of mTOR, will be used. Specific Aim 2: To test the hypothesis that mTOR
pathway activation interferes with maintenance of hyperpolarizing GABAA receptor function in the mature
brain. In Specific Aim 2, the studies of Aim 1 will be repeated in mature neuronal cultures and in adult
mice. Specific Aim 3: To define the role of the transcriptional repressor REST (RE1-Silencing
Transcription factor) in the age-dependent dysregulation of GABAergic neurotransmission by mTOR
pathway activation. We will utilize cortical neuronal cultures and lentivirus-mediated manipulation of
REST function in vivo to investigate the involvement of REST in the bidirectional regulation of KCC2
expression by mTOR pathway activation.
 As a result of these studies, we will be able to identify the differential effects of mTOR pathway
activation on inhibitory neurotransmission in immature versus mature and in male versus female brain,
thereby suggesting pathways for development of novel, targeted interventions for ASD and its
comorbidities.

## Key facts

- **NIH application ID:** 9857668
- **Project number:** 5R01MH110448-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** LAURA A JANSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $393,229
- **Award type:** 5
- **Project period:** 2018-09-18 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857668

## Citation

> US National Institutes of Health, RePORTER application 9857668, Age-Dependent Dysfunction of GABAergic Neurotransmission Due to Autism-Associated mTOR Pathway Activation (5R01MH110448-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9857668. Licensed CC0.

---

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