Abstract
Background
Duplication 15q (Dup15q) syndrome is a rare neurogenetic disorder characterized by
autism and pharmacoresistant epilepsy. Most individuals with isodicentric duplications
have been on multiple medications to control seizures. We recently developed a model
of Dup15q in Drosophila by elevating levels of fly Dube3a in glial cells using repo-GAL4, not neurons. In contrast to other Dup15q models, these flies develop seizures
that worsen with age.
Methods
We screened repo>Dube3a flies for approved compounds that can suppress seizures. Flies 3 to 5 days old were
exposed to compounds in the fly food during development. Flies were tested using a
bang sensitivity assay for seizure recovery time. At least 40 animals were tested
per experiment, with separate testing for male and female flies. Studies of K+ content in glial cells of the fly brain were also performed using a fluorescent K+ indicator.
Results
We identified 17 of 1280 compounds in the Prestwick Chemical Library that could suppress
seizures. Eight compounds were validated in secondary screening. Four of these compounds
regulated either serotonergic or dopaminergic signaling, and subsequent experiments
confirmed that seizure suppression occurred primarily through stimulation of serotonin
receptor 5-HT1A. Additional studies of K+ levels showed that Dube3a regulation of the Na+/K+ exchanger ATPα (adenosine triphosphatase α) in glia may be modulated by serotonin/dopamine
signaling, causing seizure suppression.
Conclusions
Based on these pharmacological and genetic studies, we present an argument for the
use of 5-HT1A agonists in the treatment of Dup15q epilepsy.
Keywords
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Article info
Publication history
Published online: April 13, 2020
Accepted:
April 2,
2020
Received in revised form:
March 6,
2020
Received:
November 11,
2019
Identification
Copyright
© 2020 Society of Biological Psychiatry.
