# Basal forebrain cholinergic dysfunction in sleep-related epilepsy

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $445,500

## Abstract

PROJECT SUMMARY/ABSTRACT
 The relationship between sleep and epilepsy has long been recognized. In particular, the timing of seizure
occurrence is largely correlated with sleep-wake cycles. For instance, seizures in patients with mesial temporal
lobe epilepsy (MTLE) occur more frequently during wakefulness, while patients with frontal lobe epilepsy (NFLE)
almost exclusively have seizures during NREM sleep. While hippocampal dysfunction has been proposed and
studied in MTLE, the neuropathology of NFLE remains elusive. In this proposal, we utilize a genetic mouse
model of NFLE to investigate how sleep and sleep circuits regulate seizures. Specifically, we make use of
optogenetics, fiber photometry, electrophysiology, and mouse genetics to study the role of basal forebrain
cholinergic circuitry in sleep-related epilepsy. At a fundamental level, the work proposed in this research proposal
will provide novel therapeutic targets for epilepsy treatments.
 Human genetic studies have identified several genes associated with ADNFLE (autosomal dominant NFLE),
including CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, and CRH. Several mouse models of ADNFLE are
available, notably mutations of CHRNA4 and CHRNB2. These models display abnormal excitability and are
generally accompanied by disturbed sleep. However, circuit dysfunctions have not been examined. Recently,
our co-investigator Wayne Frankel at Columbia has developed an epilepsy mouse model with a missense
mutation in KCNT1. They determined that homozygous Kcnt1 mutant mice exhibit spontaneous tonic seizures
and generalized tonic-clonic seizures. In our preliminary work to examine the relationship between sleep and
epilepsy, we observed that seizures in Kcnt1 mutants predominantly occur during NREM sleep, recapitulating
the sleep correlation in the human disease. Considering the roles of the cholinergic system in ADNFLE and sleep
regulation, we hypothesize that dysfunction of the basal forebrain (BF) cholinergic circuitry causally contribute to
sleep-related epilepsy.
 In Aim1, we will examine cell type specific neural activity of basal forebrain circuits in Kcnt1 mutant animals.
To genetically target different cell types, we will cross Kcnt1 mutants with three Cre lines (Chat-Cre, Vglut2-Cre,
Sst-Cre). Then, we will combine fiber photometry and EEG/EMG recording to compare the activity between
mutant and control animals in different brain states (i.e. wake, NREM sleep, REM sleep). Next, using axon-
targeted AAV to express GCaMP6 in Kcnt1 mutant mice we will record neural activity in the axonal terminals of
BF cholinergic neurons in the hippocampus. In Aim2, we will use closed-loop optogenetics to manipulate neural
activity of different BF cell types in Kcnt1 mutant animals to examine the causal effect of BF cholinergic
dysfunctions on sleep-related epilepsy. Specifically, we will optogenetically inhibit ChAT+ neurons or activate
SOM+ GABAergic neurons in sleep or seizures and examine whether compensating for a...

## Key facts

- **NIH application ID:** 10108368
- **Project number:** 1R21NS120027-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Yueqing Peng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $445,500
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10108368

## Citation

> US National Institutes of Health, RePORTER application 10108368, Basal forebrain cholinergic dysfunction in sleep-related epilepsy (1R21NS120027-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10108368. Licensed CC0.

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