Presynaptic FMRP and local protein synthesis support structural and functional plasticity of glutamatergic axon terminals

Monday, Hannah R.; Kharod, Shivani C.; Yoon, Yong‐Dal; Singer, Robert H.; Castillo, Pablo E.

doi:10.1016/j.neuron.2022.05.024

Cited by 49 publications

(51 citation statements)

References 112 publications

(154 reference statements)

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“…IF in the superficial dorsal horn laminae appeared more abundant than that in both deep dorsal and ventral horn laminae (Figure 2 A-C Hemi-sections and i vs ii). At high magnification, we also observed punctate staining in neuropil consistent with FMRP localization to pre-and post-synaptic processes (Akins et Christie et al, 2009;Kao et al, 2010;Monday et al, 2022b;Sawicka et al, 2019;Zimmer et al, 2017). These observations were comparable across the FMRP antibodies tested (Table 2).…”

Section: Fmrp Immunoreactivity In the Human Spinal Cordsupporting

confidence: 79%

Fragile X Mental Retardation Protein (FMRP) expression in human nociceptor axons of the spinal dorsal horn— Implications for RNA targeting and localized translation

Mitchell

Cook

Shiers

et al. 2022

Preprint

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Fragile X Mental Retardation Protein (FMRP) regulates activity-dependent RNA localization and local translation to modulate synaptic plasticity throughout the CNS. Mutations in the FMR1 gene that hinder or ablate FMRP function cause Fragile X Syndrome (FXS), a disorder associated with sensory processing dysfunction. FXS pre-mutations are associated with increased FMRP expression and neurological impairments including sex dimorphic presentations of chronic pain. In mice, FMRP ablation causes dysregulated DRG neuron excitability and synaptic vesicle exocytosis, spinal circuit activity, and decreased translation-dependent nociceptive sensitization. Activity-dependent, local translation is a key mechanism for enhancing primary nociceptor excitability which promotes pain in animals and humans. These works indicate that FMRP likely regulates nociception and pain at the level of the primary nociceptor or spinal cord. Therefore, we sought to better understand FMRP expression in the human dorsal root ganglion (DRG) and spinal cord using immunostaining in organ donor tissues. We find that FMRP is highly expressed in DRG and spinal neuron subsets with substantia gelatinosa exhibiting the most abundant immunoreactivity in spinal synaptic fields. Here, it is expressed in nociceptor axons. FMRP puncta colocalized with Nav1.7 and TRPV1 receptor signals suggesting a pool of axoplasmic FMRP localizes to plasma membrane-associated loci in these branches. Interestingly, FMRP puncta exhibited notable colocalization with calcitonin gene-related peptide (CGRP) immunoreactivity selectively in female spinal cord. Our results support a regulatory role for FMRP in human nociceptor axons of the dorsal horn and implicate it in the sex dimorphic actions of CGRP signaling in nociceptive sensitization and chronic pain.

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Section: Fmrp Immunoreactivity In the Human Spinal Cordsupporting

confidence: 79%

Fragile X Mental Retardation Protein (FMRP) expression in human nociceptor axons of the spinal dorsal horn— Implications for RNA targeting and localized translation

Mitchell

Cook

Shiers

et al. 2022

Preprint

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“…Our study, however, reveal that in mature axons of the neocortex, specific synapse types engage axonal translation to sustain release. Whether neurotransmission at specific synapse types in mature hippocampus depends on axonal translation remains unclear 1,2,25,27 . In general, however, these studies 25,27 support our findings that local axonal translation subserves critical functions even in mature axons.…”

Section: Discussionmentioning

confidence: 99%

“…Whether neurotransmission at specific synapse types in mature hippocampus depends on axonal translation remains unclear 1,2,25,27 . In general, however, these studies 25,27 support our findings that local axonal translation subserves critical functions even in mature axons. To our knowledge, our study provides the first evidence that translation in mature axons can sustain information transfer at central synapses.…”

Section: Discussionmentioning

confidence: 99%

“…Two recent studies have shown that in mature hippocampus, long-term plasticity requires presynaptic translation, putatively in axons 25,27 . Our study, however, reveal that in mature axons of the neocortex, specific synapse types engage axonal translation to sustain release.…”

Section: Discussionmentioning

confidence: 99%

“…For example, RNA docking and local protein synthesis occur in vivo at presynaptic hotspots 19 , where they may continue to play pivotal roles after circuit assembly 19–23 . Even though hundreds of different mRNAs 24 and translation machineries 17,24–27 have been found in mature presynaptic terminals, direct evidence that local translation in mature axons regulates neurotransmission is still lacking. Here, we explore this long-standing question by examining neurotransmission at mature axons from visual cortex layer-5 pyramidal cells (PCs).…”

mentioning

confidence: 99%

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Local axonal translation sustains synapse-type-specific neurotransmission

Wong

Watt

Sjöström

2022

Preprint

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Dendritic protein synthesis is a well-known regulator of neurotransmission in the central nervous system. For example, local on-demand protein synthesis in dendrites is required for hippocampal long-term1,2 and homeostatic plasticity3. Although axonal protein synthesis is a key regulator in neural circuit assembly during early development4–6, it is unclear if local translation in mature axons plays a functional role in neurotransmission of the mammalian central nervous system. Here we show that local translation in axons regulates pyramidal cell neurotransmission in primary visual cortex microcircuits in a synapse-type-specific manner7,8. Using paired recordings to manipulate pre- and postsynaptic neurons independently, we found that presynaptic translation sustains neurotransmission and regulates short-term plasticity. This was mediated via mTOR and cap-dependent translation, with presynaptic NMDA receptors acting as an up-stream trigger. By isolating the axon from the soma with laser microsurgery, we unveiled that axonal translation was required to sustain neurotransmission. With live endogenous RNA imaging, we found that RNA granules stably docked in individual presynaptic compartments, suggesting bouton-specific regulation. In agreement, presynaptic translation influenced pyramidal cell synapses to neighbouring pyramidal cells, but not to inhibitory Martinotti cells. Our study establishes local protein synthesis in mature axons as a fundamental regulatory principle that governs information transfer at central synapses.

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Characterization of Fragile X Mental Retardation Protein expression in human nociceptors and their axonal projections to the spinal dorsal horn

Mitchell

Cook

Shiers

et al. 2023

J of Comparative Neurology

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Fragile X Mental Retardation Protein (FMRP) regulates activity‐dependent RNA localization and local translation to modulate synaptic plasticity throughout the central nervous system. Mutations in the FMR1 gene that hinder or ablate FMRP function cause Fragile X Syndrome (FXS), a disorder associated with sensory processing dysfunction. FXS premutations are associated with increased FMRP expression and neurological impairments including sex dimorphic presentations of chronic pain. In mice, FMRP ablation causes dysregulated dorsal root ganglion (DRG) neuron excitability and synaptic vesicle exocytosis, spinal circuit activity, and decreased translation‐dependent nociceptive sensitization. Activity‐dependent, local translation is a key mechanism for enhancing primary nociceptor excitability that promotes pain in animals and humans. These works indicate that FMRP likely regulates nociception and pain at the level of the primary nociceptor or spinal cord. Therefore, we sought to better understand FMRP expression in the human DRG and spinal cord using immunostaining in organ donor tissues. We find that FMRP is highly expressed in DRG and spinal neuron subsets with substantia gelatinosa exhibiting the most abundant immunoreactivity in spinal synaptic fields. Here, it is expressed in nociceptor axons. FMRP puncta colocalized with Nav1.7 and TRPV1 receptor signals suggesting a pool of axoplasmic FMRP localizes to plasma membrane‐associated loci in these branches. Interestingly, FMRP puncta exhibited notable colocalization with calcitonin gene‐related peptide (CGRP) immunoreactivity selectively in female spinal cord. Our results support a regulatory role for FMRP in human nociceptor axons of the dorsal horn and implicate it in the sex dimorphic actions of CGRP signaling in nociceptive sensitization and chronic pain.

show abstract

Presynaptic FMRP and local protein synthesis support structural and functional plasticity of glutamatergic axon terminals

Cited by 49 publications

References 112 publications

Fragile X Mental Retardation Protein (FMRP) expression in human nociceptor axons of the spinal dorsal horn— Implications for RNA targeting and localized translation

Fragile X Mental Retardation Protein (FMRP) expression in human nociceptor axons of the spinal dorsal horn— Implications for RNA targeting and localized translation

Local axonal translation sustains synapse-type-specific neurotransmission

Characterization of Fragile X Mental Retardation Protein expression in human nociceptors and their axonal projections to the spinal dorsal horn

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