Authors :
Presenting Author: Manuel Silva-Pérez, PhD – Baylor College of Medicine
Jin Park, MS – Neuroscience – Baylor College of Medicine; Jeannie Chin, PhD – Neuroscience – Baylor College of Medicine
Rationale:
Patients with Alzheimer’s disease (AD) have an increased incidence of epilepsy, which may contribute to cognitive decline. However, this relationship is often underestimated due to the prevalence of non-convulsive seizures and their preferential occurrence during sleep. Several mouse models of AD-related neuropathology also develop epileptiform spikes and seizures predominantly during sleep. The mechanisms that underlie the increased susceptibility to epileptiform activity during sleep in AD are unclear.
Norepinephrine, a neuromodulator reported to have antiepileptic effects, exhibits a pattern that is opposite of AD-related epileptiform activity: norepinephrine abundance is low during sleep and high during wakefulness. We hypothesized that norepinephrine dynamics could explain the preferential occurrence of epileptiform activity during sleep, and that enhancing norepinephrine availability may show therapeutic potential. To test this hypothesis, we used norepinephrine reuptake inhibitors or chemogenetic stimulation of the locus coeruleus to enhance norepinephrine tone in amyloid precursor protein (APP) transgenic mice, and studied their impacts on epileptiform activity throughout the sleep-wake cycle.
Methods:
We performed EEG recordings in female and male APP mice in baseline conditions, after injection of vehicle control, and after injection with the norepinephrine reuptake inhibitors desipramine or reboxetine. Epileptiform spikes were quantified, and sleep scoring was performed to assess epileptiform spike rates across the sleep-wake cycle. As a complementary strategy, we used chemogenetics to stimulate the locus coeruleus in APP mice that expressed Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) specifically in the locus coeruleus. For those experiments, AAV2-hSyn-DIO-hM3Dq-mCherry was bilaterally infused into the locus coeruleus of APP mice crossed with transgenic DBH-Cre mice, and allowed to express for at least three weeks. EEG was recorded in baseline conditions, after administration of vehicle, and after treatment with agonists clozapine N-oxide (CNO) or deschloroclozapine (DCZ). Epileptiform spikes and the sleep-wake cycle were then assessed.
Results:
Both the treatment with norepinephrine reuptake inhibitors and the chemogenetic stimulation of the locus coeruleus led to acute and reversible decreases in spike abundance in APP mice, especially during NREM sleep. Effects were most pronounced shortly after administration and gradually subsided over the course of several hours. These results demonstrate that norepinephrine levels influence the abundance epileptiform activity in APP mice.
Conclusions:
Our results demonstrate that increasing norepinephrine availability through two different strategies effectively reduces epileptiform activity in APP mice in a sleep-wake state-dependent manner. Therefore, norepinephrine enhancement may be a compelling therapeutic avenue in the context of AD-related epilepsy.
Funding:
Supported by a grant from the American Epilepsy Society (MSP) and grants NS085171 and AG065290 from the National Institutes of Health (JC).