# Synaptic changes and hypersynchronous network activity in mTORopathies

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $343,357

## Abstract

Project Summary
Genetic variants that hyperactivate mechanistic target of rapamycin (mTOR) signaling are among the most
common pathological substrates associated with intractable pediatric epilepsy, and hyperactivation of the
mTOR pathway is also proposed to mediate epileptogenesis in response to brain injury. Although altered
neuronal migration and morphology are hallmarks of many known mTOR-related neurological diseases
(mTORopathies) in humans, studies in animal models show that abnormal synaptic transmission and network
activity precede or occur in the absence of overt structural changes, and that preventing structural changes
does not prevent the neurological symptoms. This highlights the need for a better understanding of the
functional changes in the brain. This proposal will test the hypothesis that abnormal synchronous neuronal
activity caused by genetic hyperactivation of the mTOR signaling pathway is driven by changes in synaptic
transmission. The long-term goal is to understand the genesis of, and then prevent or rescue, this abnormal
activity, which may underlie both the high incidence of epilepsy and autism in humans with mTORopathies.
In Aim 1, we will address this by testing four genetic models of mTORopathies (Tsc1, Pten, Pik3ca, Szt2) and
determining whether there are common synaptic changes. Whether different mTORopathies share common
synaptic alterations is an essential question to understanding the mechanistic similarity of these molecularly
related diseases. In Aim 2, we will use molecular genetic rescue strategies that dissociate the morphological
and synaptic effects of mTOR hyperactivation to test whether synaptic changes are sufficient to induce
hypersynchronous activity and epilepsy. In Aim 3, we will use a combination of widefield and 2-photon calcium
imaging to track the development and characteristics of hypersynchronous activity in vivo. We will then test
whether the synaptic changes we observe in vitro are present at the time and place of hypersynchronous
activity onset, and whether they can drive aberrant network activity. We anticipate that defining the functional
consequences of mTOR hyperactivation relevant to enhanced neuronal excitability will lead to significant
advances in the understanding of disease mechanisms, and aid the development of treatment strategies for
mTORpathies and other neurological diseases.

## Key facts

- **NIH application ID:** 9852558
- **Project number:** 5R01NS110945-02
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Matthew C Weston
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,357
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852558

## Citation

> US National Institutes of Health, RePORTER application 9852558, Synaptic changes and hypersynchronous network activity in mTORopathies (5R01NS110945-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852558. Licensed CC0.

---

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