An Unbiased Drug Screen for Seizure Suppressors in Duplication 15q Syndrome Reveals 5-HT1A and Dopamine Pathway Activation as Potential Therapies

Roy, Bidisha; Han, Jungsoo; Hope, Kevin A.; Peters, Tracy L.; Palmer, Glen E.; Reiter, Lawrence T.

doi:10.1016/j.biopsych.2020.03.021

Cited by 9 publications

(12 citation statements)

References 86 publications

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“…Demonstrating that serotonin signaling is affected in fly models for brain disorders, is not only relevant for advancing our understanding of the underpinnings of these illnesses, it also opens up the possibility to carry out a high-throughput search for new chemicals that affect specific phenotypes in flies, which could eventually lead to new therapeutic tools for these disorders ( Nichols, 2006 ; Roy et al, 2020 ).…”

Section: Drosophila As Animal Model For the Study Of Neurodementioning

confidence: 99%

Studying the Contribution of Serotonin to Neurodevelopmental Disorders. Can This Fly?

Carvajal-Oliveros

Campusano

2021

Front. Behav. Neurosci.

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Serotonin is a biogenic amine that acts as neurotransmitter in different brain regions and is involved in complex behaviors, such as aggression or mood regulation. Thus, this amine is found in defined circuits and activates specific receptors in different target regions. Serotonin actions depend on extracellular levels of this amine, which are regulated by its synthetic enzymes and the plasma membrane transporter, SERT. Serotonin acts also as a neurotrophic signal in ontogeny and in the mature brain, controlling cell proliferation, differentiation, neurogenesis, and neural plasticity. Interestingly, early alterations in serotonergic signaling have been linked to a diversity of neurodevelopmental disorders, including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), or mental illnesses like schizophrenia or depression. It has been proposed that given the complex and numerous actions of serotonin, animal models could better serve to study the complexity of serotonin actions, while providing insights on how hindering serotonergic signaling could contribute to brain disorders. In this mini-review, it will be examined what the general properties of serotonin acting as a neurotransmitter in animals are, and furthermore, whether it is possible that Drosophila could be used to study the contribution of this amine to neurodevelopmental and mental disorders.

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Section: Drosophila As Animal Model For the Study Of Neurodementioning

confidence: 99%

Studying the Contribution of Serotonin to Neurodevelopmental Disorders. Can This Fly?

Carvajal-Oliveros

Campusano

2021

Front. Behav. Neurosci.

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“…Elevation of overall 5-HT levels, 5-HT1A receptor agonists or antagonists of 5-HT2A receptors reduce recovery time in repo > dube3a flies, while 5-HT1A antagonists and 5-HT2A agonists increase recovery time of repo>dube3a flies (B. Roy et al, 2020). We selected two drugs from the previous screen, ketanserin and vortioxetine, to determine if either compound could attenuate spontaneous and heat-induced seizure-associated behavior in repo>dube3a flies.…”

Section: Resultsmentioning

confidence: 99%

“…A previous screen for compounds ameliorating mechanical shock-induced seizure activity (BSA) in repo>dube3a flies uncovered several modulators of serotonin (5-HT) neurotransmission which significantly shorten the recovery time following mechanical shock (Bidisha Roy et al, 2020). In fact, Dube3a can regulate monoamine synthesis through transcriptional regulation of GTP cyclohydrolase I (F. Ferdousy et al, 2011) and in mouse models of UBE3A related syndromes, Ube3a can modulate 5HT levels in some regions of the brain (Farook et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

“…Neuronal overexpression of UBE3A in mouse models of Dup15q syndrome recapitulate some aspects of the repetitive stereotypic behavior and defective social interaction characteristic of the disease (Copping et al, 2017; Takumi, 2011), however spontaneous seizure phenotypes have not been reported in these models. In flies, overexpression of dube3a in glia, but not neurons, causes bang-sensitive hyperexcitable phenotypes (Hope et al, 2017; Roy et al, 2020). Indeed, in the context of other epilepsy syndromes, there is growing appreciation of the role of glia in contributing to associated pathophysiology (Tian et al, 2005; Kang et al, 2005; Steinhauser et al, 2012; Patel et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Hope et al, 2017; B. Roy et al, 2020). This seizure-like activity is reminiscent of other fly mutants ( FAK, ATPa, zydeco ,) where glial disfunction is thought to contributed to behavioral phenotypes (Hope et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Glial expression ofDrosophila UBE3Acauses spontaneous seizures modulated by 5-HT signaling

Sleep,

Landaverde,

Lacoste

et al. 2024

Preprint

Self Cite

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Misexpression of the E3 ubiquitin ligaseUBE3Ais thought to contribute to a range of neurological disorders. In the context of Dup15q syndrome, excess genomic copies ofUBE3Ais thought to contribute to the autism, muscle tone and spontaneous seizures characteristic of the disorder. In a Drosophila model of Dup 15q syndrome, it was recently shown glial-driven expression of theUBE3Aortholog dube3a led to a "bang-sensitive" phenotype, where mechanical shock triggers convulsions, suggesting glial dube3a expression contributes to hyperexcitability in flies. Here we directly compare the consequences of glial- and neuronal-drivendube3aexpression on motor coordination and neuronal excitability in Drosophila. We utilized IowaFLI tracker and developed a hidden Markov Model to classify seizure-related immobilization. Both glial and neuronal drivendube3aexpression led to clear motor phenotypes. However, only glial-driven dube3a expression displayed spontaneous immobilization events, that were exacerbated at high-temperature (38 °C). Using a tethered fly preparation we monitored flight muscle activity, we found glial-drivendube3aflies display spontaneous spike discharges which were bilaterally synchronized indicative of seizure activity. Neither control flies, nor neuronal-dube3a overexpressing flies display such firing patterns. Prior drug screen indicated bang-sensitivity in glial-driven dube3a expressing flies could be suppressed by certain 5-HT modulators. Consistent with this report, we found glial-drivendube3aflies fed the serotonin reuptake inhibitor vortioxetine and the 5HT2A antagonist ketanserin displayed reduced immobilization and spike bursting. Together these findings highlight the potential for glial pathophysiology to drive Dup15q syndrome-related seizure activity.

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5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk?

Dourron,

Nichols,

Simonsson

et al. 2023

Psychopharmacology

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An Unbiased Drug Screen for Seizure Suppressors in Duplication 15q Syndrome Reveals 5-HT1A and Dopamine Pathway Activation as Potential Therapies

Cited by 9 publications

References 86 publications

Studying the Contribution of Serotonin to Neurodevelopmental Disorders. Can This Fly?

Studying the Contribution of Serotonin to Neurodevelopmental Disorders. Can This Fly?

Glial expression ofDrosophila UBE3Acauses spontaneous seizures modulated by 5-HT signaling

5-MeO-DMT: An atypical psychedelic with unique pharmacology, phenomenology & risk?

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