# The role of beta-catenin in the pathophysiology of infantile spasms

> **NIH NIH R01** · TUFTS UNIVERSITY BOSTON · 2020 · $496,517

## Abstract

Project summary
Infantile spasms (IS, also known as West Syndrome) is a catastrophic childhood epilepsy syndrome
characterized by spasms which progress into seizures later in life. Spasms are typified by spontaneous
flexion/extension of the head, neck, and limbs and occur first between 4 and 8 months of age. The current
treatment options for IS are often ineffective and are associated with significant side effects. Therefore, novel
treatment strategies are essential. One limiting factor in identifying new treatment approaches is a paucity of
pre-clinical animal models. We have identified and characterized a novel rodent model with many phenotypic
characteristics of human IS. The model was generated by breeding male mice containing a floxed version of
the Adenomatous polyposis coli (APC) gene with female mice expressing the Cre-recombinase gene under the
control of the Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIa) promoter. The offspring of this
cross, which lack APC in CaMKIIa-positive neurons, are known as APC conditional knockouts (APC cKOs).
APC cKO animals have been shown to have increased excitatory synaptic communication and an increased
density of excitatory spines on hippocampal CA1 pyramidal neurons. APC is the main inhibitory regulator of a
large signaling pathway known as the β-catenin/Wnt pathway. APC is part of the β-catenin destruction
complex, targeting β-catenin for degradation. When APC is lost, β-catenin levels rise and 1) increase
transcription of a large family of genes, and 2) increase the stability of excitatory synapses. We began by
examining APC cKO animals for phenotypes consistent with human IS. We found that they exhibit
spontaneous behavioral spasms at postnatal days 8-11, they have an ictal EEG correlate of spasm behavior
similar to human ictal activity in IS, and as adults, they have spontaneous electrographic and behavioral
seizures. Interestingly, APC heterozygous mutations in humans are linked to both developmental and seizure
disorders. Furthermore, many of the genes linked to IS are either part of the β-catenin/Wnt pathway or are
reciprocally regulated by it. In this proposal, we will specifically examine the role of β-catenin in the
pathophysiology of infantile spasms. We will examine the effects of increasing β-catenin (by deleting APC and
independently of APC) on spasm behavior, seizures, and electrographic brain activity. Next, we will perform
careful pharmacokinetic, pharmacodynamic, and adverse effect analysis of manipulating β-catenin during
development with a drug called G007-LK. Lastly, we will determine if restoring β-catenin levels to normal
attenuates spasms and seizures later in life. This proposal will address the role of β-catenin in the
pathophysiology of spasms, provide a new mouse model for pre-clinical analysis, and introduce a large set of
new potential therapeutic targets for the treatment of IS.

## Key facts

- **NIH application ID:** 9828110
- **Project number:** 5R01NS100706-03
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Chris G Dulla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $496,517
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828110

## Citation

> US National Institutes of Health, RePORTER application 9828110, The role of beta-catenin in the pathophysiology of infantile spasms (5R01NS100706-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828110. Licensed CC0.

---

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