AI Summary
This research study explores the role of electrical synapses in mediating hyperactivity in a zebrafish model of Fragile X syndrome. The study found that Fragile X syndrome model mutant zebrafish exhibit hyperexcitability from the earliest stages of spontaneous behavior, have altered responses to blocking electrical gap junctions, and show increased expression of gap junction protein Connexin 34/35. The researchers were able to rescue hyperexcitable behavior by inhibiting electrical synapses pharmacologically. Functional imaging revealed that disruption of electrical gap junctions impacts the activity between motor neurons and interneurons during early embryonic development. This study emphasizes the importance of electrical synapses in motor development and suggests that hyperactivity in neurodevelopmental disorders may have origins in the early formation of locomotive circuits.
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 (MNs) 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 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 MN and interneuron (IN) activity in early embryogenesis, finding genetic disruption of electrical gap junctions uncouples activity between mnx1+ MNs and INs. 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.