# Role of CACHD1 in the development of temporal lobe epilepsy and absence epilepsy

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $399,015

## Abstract

Epilepsy is a major economic and personal burden for the American public, affecting over 3 million
Americans (1-2% of the population) with over 200,000 new cases diagnosed each year. There is no cure for
epilepsy. Seizures can only be suppressed using antiepileptic drugs. Unfortunately, these drugs are ineffective
in approximately 30% of patients and are often associated with adverse side effects.
 T-type calcium channels (T-channels) play an important role in controlling neuronal excitability. T-
channels open near the resting membrane potential of many neurons, allowing them to act as pacemaker
currents that trigger sodium dependent action potential. Increases in T-channel expression and activity have
been reported in animal models of temporal lobe epilepsy (TLE), contributing to neuronal hyperexcitability. In
absence epilepsy, T-channel activity has been linked to thalamocortical network oscillations that give rise to
spike wave discharges (SWD). Despite growing evidence for a role of T-channels in both TLE and absence
epilepsy, little is known about the mechanisms by which T-channel activity and expression levels are increased,
facilitating increases in neuronal excitability and seizure susceptibility. We recently discovered a novel T-channel
modulator, the Ca2+ channel and chemotaxis receptor domain containing 1 (CACHD1) protein. CACHD1 is
structurally similar to 2 subunits, the major target of gabapentinoids. CACHD1 is highly expressed in both
human and rodent hippocampal and thalamic brain regions with overlapping expression patterns to all three T-
channel subtypes. CACHD1 promotes cell surface expression levels of T-channels and increases peak current
densities, leading to an increase in neuronal excitability and increased seizure susceptibility. Knockout of
CACHD1 prevents γ-butyrolactone (GBL) induced absence seizures and delays the onset of kindled seizures
and reduces seizure durations. In view of these findings, CACHD1 could facilitate increases in neuronal
excitability associated with TLE and absence epilepsy, making it a novel target for therapy. In this proposal we
will test our central hypothesis that CACHD1 increases neuronal excitability via increases in T-channel
function, facilitating the onset and severity of both absence epilepsy and TLE. On completion of these
studies we will have advanced our current understanding for the role of CACHD1 in the development of absence
epilepsy and TLE, providing a novel target for therapy development.

## Key facts

- **NIH application ID:** 10298252
- **Project number:** 1R01NS120702-01A1
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** MANOJ K PATEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,015
- **Award type:** 1
- **Project period:** 2021-07-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298252

## Citation

> US National Institutes of Health, RePORTER application 10298252, Role of CACHD1 in the development of temporal lobe epilepsy and absence epilepsy (1R01NS120702-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10298252. Licensed CC0.

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