PUBLICATION
Electrical synapses mediate embryonic hyperactivity in a zebrafish model of Fragile X syndrome
- Authors
- Miles, K.D., Barker, C.M., Russell, K.P., Appel, B.H., Doll, C.A.
- ID
- ZDB-PUB-240707-8
- Date
- 2024
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 44(31): (Journal)
- Registered Authors
- Appel, Bruce
- Keywords
- none
- MeSH Terms
-
- Animals
- Gap Junctions/drug effects
- Gap Junctions/metabolism
- Animals, Genetically Modified
- Hyperkinesis/physiopathology
- Disease Models, Animal
- Interneurons/metabolism
- Interneurons/physiology
- Fragile X Mental Retardation Protein/genetics
- Fragile X Mental Retardation Protein/metabolism
- Electrical Synapses*/physiology
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Motor Neurons*/physiology
- Fragile X Syndrome*/genetics
- Fragile X Syndrome*/physiopathology
- Connexins/genetics
- Connexins/metabolism
- Zebrafish*
- PubMed
- 38969506 Full text @ J. Neurosci.
Citation
Miles, K.D., Barker, C.M., Russell, K.P., Appel, B.H., Doll, C.A. (2024) Electrical synapses mediate embryonic hyperactivity in a zebrafish model of Fragile X syndrome. The Journal of neuroscience : the official journal of the Society for Neuroscience. 44(31):.
Abstract
Although hyperactivity is associated with a wide variety of neurodevelopmental disorders, the early embryonic origins of locomotion have hindered investigation of pathogenesis of these debilitating behaviors. The earliest motor output in vertebrate animals is generated by clusters of early-born motor neurons that occupy distinct regions of the spinal cord, innervating stereotyped muscle groups. Gap junction electrical synapses drive early spontaneous behavior in zebrafish, prior to the emergence of chemical neurotransmitter networks. We use a genetic model of hyperactivity to gain critical insight into the consequences of errors in motor circuit formation and function, finding that Fragile X syndrome (FXS) model mutant zebrafish are hyperexcitable from the earliest phases of spontaneous behavior, show altered sensitivity to blockade of electrical gap junctions, and have increased expression of the gap junction protein Connexin 34/35. We further show that this hyperexcitable behavior can be rescued by pharmacological inhibition of electrical synapses. We also use functional imaging to examine motor neuron and interneuron activity in early embryogenesis, finding genetic disruption of electrical gap junctions uncouples activity between mnx1+ motor neurons and interneurons. Taken together, our work highlights the importance of electrical synapses in motor development and suggests that the origins of hyperactivity in neurodevelopmental disorders may be established during the initial formation of locomotive circuits.Significance Statement The origins of hyperactivity in neurodevelopmental disorders are difficult to pinpoint in vertebrate systems. Zebrafish locomotive circuits initiate in early embryogenesis, with defined motor neurons and interneurons driving the earliest locomotive movements. Using a genetic model of hyperactivity, we show that Fragile X syndrome model fmr1 mutant embryos display hyperexcitable behavior and express excess gap junction connexin proteins on motor circuit neurons. We further show that this hyperexcitable behavior can be rescued by pharmacological inhibition of electrical synapses. Taken together, this data suggests hyperactive behavior initiates in the earliest phases of neurodevelopment.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping