# The Circadian Molecular Clock is a Biomarker for Epilepsy in Focal Cortical Dysplasia

> **NIH NIH R01** · BROWN UNIVERSITY · 2020 · $354,635

## Abstract

Scientific Abstract: A common heterogeneous non-inherited condition, focal cortical dysplasia (FCD), is the
most common cause of refractory focal epilepsy. While FCD is presumably a stable developmental
malformation, epilepsy onset is variable and cases of non-epileptogenic FCD are reported. What factors initiate
epilepsy in FCD are unknown. Nevertheless, in pediatric epilepsy most therapeutic resections are performed
for FCD patients with severely medically refractory seizures. The tissue collected from this procedure allowed
us to study epileptogenesis in these cortical malformations. To discover molecular pathways and to identify
potential therapeutic targets in epilepsy, we banked resections and performed a transcriptome analysis of the
epileptogenic tissue from FCD and a related disorder Tuberous Sclerosis Complex (TSC).
 Our preliminary transcriptome analysis on surgical samples from intractable focal epilepsy surgical
cases included patients with focal cortical dysplasia (FCD) and tuberous sclerosis complex (TSC). The
statistical analysis of gene expression in that study identified a decrease in the mRNA levels of the
transcription factor, Circadian Locomotor Output Cycles Kaput (Clock), expression in epileptogenic tissue from
both FCD and TSC compared with non-epileptic brain. This result was confirmed by Western analysis in a
larger cohort of FCD cases. We found a reduction of Clock in both excitatory and inhibitory neurons. We
created mouse lines with selective deletion of Clock in either excitatory neurons in the cortex or inhibitory
neurons. We found that mice with specific deletion of the Clock gene in excitatory neurons have spontaneous
seizures. Based on these results we hypothesize loss of Clock disrupts downstream gene expression leading
to circuit dysfunction and epilepsy. Conversely, maintenance of Clock function prevents circuit and molecular
changes causative for epilepsy. We will test this hypothesis in three aims:
 1) We will determine the effect of Clock loss of function on cortical microcircuits. 2) We will determine a
molecular mechanism for Clock by studying its targets, the PARbZip transcription factors. 3) We will use small
molecule modifiers of circadian transcription genetic techniques to rescue the effects of decreased Clock. This
approach has the potential to improve epilepsy care by developing new therapeutic strategies and refining
epilepsy biomarkers.

## Key facts

- **NIH application ID:** 9849816
- **Project number:** 5R01NS104428-02
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Judy Shih-Hwa Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,635
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849816

## Citation

> US National Institutes of Health, RePORTER application 9849816, The Circadian Molecular Clock is a Biomarker for Epilepsy in Focal Cortical Dysplasia (5R01NS104428-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9849816. Licensed CC0.

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