Fmrp regulates neuronal balance in embryonic motor circuit formation

Barker, Chase M.; Miles, Kaleb Dee; Doll, Caleb A.

doi:10.3389/fnins.2022.962901

Cited by 4 publications

(4 citation statements)

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“…An earlier study by the same group analyzed metabolic indicators in Fmr1 KO mice 58 and found a lack of differences in glucose levels, which is in agreement with our study, but reported differences in serum lipid profile, leptin and insulin. Our study may be in agreement with a study using a zebrafish model of Fmr1 deletion, that determined developmental defects in the motor cortex, which may lead to changes in locomotion 59 . Also in agreement with our results here, decreased locomotion in the Fmr1 KO mice on the C57 background was reported before, in a report that demonstrated that reduced movement is due to reduced forward locomotion and bout onsets 43 .…”

Section: Discussionsupporting

confidence: 92%

Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction

Ruggiero-Ruff,

Villa,

Hijleh

et al. 2023

Sci Rep

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Mutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene are linked to Fragile X Syndrome, the most common monogenic cause of intellectual disability and autism. People affected with mutations in FMR1 have higher incidence of obesity, but the mechanisms are largely unknown. In the current study, we determined that male Fmr1 knockout mice (KO, Fmr1−/y), but not female Fmr1−/−, exhibit increased weight when compared to wild-type controls, similarly to humans with FMR1 mutations. No differences in food or water intake were found between groups; however, male Fmr1−/y display lower locomotor activity, especially during their active phase. Moreover, Fmr1−/y have olfactory dysfunction determined by buried food test, although they exhibit increased compulsive behavior, determined by marble burying test. Since olfactory brain regions communicate with hypothalamic regions that regulate food intake, including POMC neurons that also regulate locomotion, we examined POMC neuron innervation and numbers in Fmr1−/y mice. POMC neurons express Fmrp, and POMC neurons in Fmr1−/y have higher inhibitory GABAergic synaptic inputs. Consistent with increased inhibitory innervation, POMC neurons in the Fmr1−/y mice exhibit lower activity, based on cFOS expression. Notably, Fmr1−/y mice have fewer POMC neurons than controls, specifically in the rostral arcuate nucleus, which could contribute to decreased locomotion and increased body weight. These results suggest a role for Fmr1 in the regulation of POMC neuron function and the etiology of Fmr1-linked obesity.

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Section: Discussionsupporting

confidence: 92%

Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction

Ruggiero-Ruff,

Villa,

Hijleh

et al. 2023

Sci Rep

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“…Importantly, electrical coupling remains influential in more mature stages 48,49,74 , which suggests gap junctions could exert a persistent influence on hyperactivity in this FXS model. The emergence of chemical neurotransmission may also contribute to hyperactive locomotion phenotypes in FXS, as we've previously shown reduced expression of inhibitory synaptic machinery in fmr1 embryos at the end of embryogenesis 50 . Therefore, inhibitory INs in our FXS model may have reduced influence as locomotive activity progresses into more complex swimming behavior.…”

Section: Discussionmentioning

confidence: 95%

“…To test this possibility, we used an antibody raised against the neuronal gap junction protein Connexin 36 (Cx36), which detects Connexins encoded by multiple genes in zebrafish 48,49 . We detected Cx36 expression in whole-mount wild-type and fmr1 mutant embryos expressing the mnx1:EGFP transgene in these experiments to clearly label early motor units (Figure 6A,B), and used a three-dimensional surface modeling strategy to distinguish Cx36 punctal expression that was specifically localized to motor circuit neurons 50 . We first examined Cx36 expression at 17 hpf, just prior to most MN axogenesis and the initiation of spontaneous behavior, finding no change in Cx36 density on mnx1 + somata in fmr1 embryos, when normalized to the relative volume of mnx1:EGFP (Figure 6B,C).…”

Section: Increased Expression Of Connexin 36 In the Absence Of Fmrp I...mentioning

confidence: 99%

“…Graphs show complete movement frequency (C; control=0.11±0.02 Hz; [50]=0.12±0.03 Hz; [100]=0.01±0.01 Hz), weak movement frequency (D; control=0±0 Hz; [50]=0.12±0.02 Hz; [100]=0.03±0.01 Hz), and cumulative movement frequency (E; control=0.11±0.02 Hz; [50]=0.24±0.03 Hz; [100]=0.04±0.02 Hz; significance by ANOVA tests with Dunnett's multiple comparison tests. n Control =15 embryos; n[50] =16; n[100] =17. See Videos 1-3.…”

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confidence: 99%

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Synchronicity in zebrafish locomotive circuit development mediated by electrical pacemaker interneurons

Miles,

Barker,

Appel

et al. 2023

Preprint

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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. Even the simplest movements require coordinated activity across these motor pools, yet motor neurons are not directly interconnected and instead project to the periphery. Instead, emerging motor circuits might be synchronized by pacemaker interneurons. We hypothesize that pacemaker interneurons are required for synchronization of motor neuron activity throughout the spinal cord, coupling motor pools through electrical gap junctions to ultimately drive coordinated motor behavior. With functional imaging in the embryonic zebrafish spinal cord, we show that ipsilateral caudal interneurons possess periodic activity profiles prior to widespread motor circuit activity that transition to synchronized Ca2+events in motor neurons throughout the spinal cord. Importantly, we also show that blockade of electrical gap junctions and ablation of pioneer pacemakers leads to desynchronization in developing motor circuits. Further, 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 reduced sensitivity to blockade of electrical gap junctions, and have increased expression of the gap junction protein Connexin 36. Taken together, our work highlights the importance of pacemakers in the development of motor circuits and suggests that the origins of hyperactivity in neurodevelopmental disorders may be established during the initiation of motor circuit formation.

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Electrical Synapses Mediate Embryonic Hyperactivity in a Zebrafish Model of Fragile X Syndrome

Miles,

Barker,

Russell

et al. 2024

J. Neurosci.

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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 betweenmnx1+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 StatementThe 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 modelfmr1mutant 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.

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Fmrp regulates neuronal balance in embryonic motor circuit formation

Cited by 4 publications

References 70 publications

Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction

Increased body weight in mice with fragile X messenger ribonucleoprotein 1 (Fmr1) gene mutation is associated with hypothalamic dysfunction

Synchronicity in zebrafish locomotive circuit development mediated by electrical pacemaker interneurons

Electrical Synapses Mediate Embryonic Hyperactivity in a Zebrafish Model of Fragile X Syndrome

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