# Molecular Mechanism of Hippocampal network excitability in a novel, in vivo model of Tuberous Sclerosis Complex

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2021 · $335,999

## Abstract

PROJECT SUMMARY
Overview: The project focuses on understanding the molecular basis of how disrupted calcium homeostasis
leads to disrupted hippocampal network activity that results in maladaptive responses in neurons with TSC
deficient signaling.
Approximately 33% of children who have autism spectrum disorder (ASD) also have epilepsy. Early childhood
seizures can result in compromised synaptic plasticity and cognitive impairment, suggesting that the
hippocampus may be vulnerable to changes in network excitability. Despite the importance of this problem, the
connection between seizure activity and development of ASD is poorly understood. Mammalian Target of
rapamycin (mTOR) is a kinase that regulates protein synthesis and is overactive in many complex brain
disorders. In the proposed studies, we focus on a mouse model of ASD, Tuberous Sclerosis Complex (TSC),
which is a disorder that results from mutations in either the tsc1 or 2 genes. We propose that deficient TSC
signaling leads to overactive mTOR and deficient protein synthesis that manifests as epilepsy and ASD. There
is no cure for TSC, treatments are limited, and new therapeutic targets are needed. Our previous work has
demonstrated that mTOR activity represses the expression of epilepsy-linked ion channels. The proposed
studies extend our work to address the molecular mechanisms underlying hippocampal network
hyperexcitability in TSC. We will take a multidisciplinary approach to critically test the prediction that reduced
expression of the voltage-gated calcium channel subunit α2∂2 by overactive mTOR signaling in TSC leads to
dysregulated calcium homeostasis and aberrant hippocampal network activity. (1) At the molecular level, we
ask how α2∂2 expression is regulated by mTOR; (2) at the cellular level, we ask what is α2∂2’s role in dendritic
calcium signaling and glutamate receptor recycling in TSC deficient dendrites; and (3) at the network level, we
address the effect of α2∂2 in promoting aberrant hippocampal network activity. The proposed work is the first
to bridge the gap between underlying molecular/cellular mechanisms and hippocampal network
hyperexcitability in TSC, using a novel preclinical model to measure spike and seizure threshold for the first
time. The strength of our approach allows us to also test several interventions using our novel optogenetic
preclinical model of network activity. Notably, seizure medications do not target only the region of the brain that
seizures originate, but can reduce hyperexcitable neurons in other parts of the brain, such as the hippocampus
where ASD is tightly linked. Thus, we hypothesize that the hippocampus is vulnerable in children with TSC due
to neuronal and network hyperexcitabillity. These studies form the foundation for promising new therapeutic
strategies for TSC and other mTOR-related, complex brain disorders, with possible clinical applications.

## Key facts

- **NIH application ID:** 10188655
- **Project number:** 5R01NS105005-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Kimberly Frances Raab-Graham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $335,999
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188655

## Citation

> US National Institutes of Health, RePORTER application 10188655, Molecular Mechanism of Hippocampal network excitability in a novel, in vivo model of Tuberous Sclerosis Complex (5R01NS105005-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10188655. Licensed CC0.

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