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:10.2139/ssrn.3917211

Cited by 2 publications

(11 citation statements)

References 74 publications

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“…FMRP signal that colocalized with peripherin IF was predominantly punctate for the three FMRP antibodies ( Figure 3 A-C Boxes ). This was consistent with axonal FMRP-RNP staining in human and rodent brain tissues (Akins et al, 2017; Christie et al, 2009; Chyung et al, 2018; Gingrich et al, 2018; Monday et al, 2022b). This indicates that FMRP is present in the central branches of human DRG neurons and suggests that it is likely also present in the presynaptic structures of these axons in the spinal cord.…”

Section: Resultssupporting

confidence: 84%

“…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 al, 2017; 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: Resultssupporting

confidence: 74%

“…We immunostained for FMRP in adult human spinal cord sections exactly as we did in DRG ( Figure 2 ; Tables 1 and 2 ). We found that each FMRP antibody exhibited IF signal in neuronal cell bodies present throughout the grey matter ( Figure 2 A-C ) (Akins et al, 2017; Christie et al, 2009; Kao et al, 2010; Monday et al, 2022b; Sawicka et al, 2019; Zimmer et al, 2017). 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 ).…”

Section: Resultsmentioning

confidence: 91%

“…Therefore, we asked whether FMRP IF in nociceptor spinal branches localizes to specific axonal microdomains in human spinal cord ( Figure 5 ). To do this, we took advantage of the well-established punctate morphology FMRP IF signal in axons (see methods) and the size of primary nociceptor arbors in the dorsal root of human spinal cord (Akins et al, 2017; Christie et al, 2009; Chyung et al, 2018; Gingrich et al, 2018; Monday et al, 2022b). On average, we found that these arbors were roughly 3 μm wide by peripherin staining (cross sectional and short longitudinal axes) ( Figure 5 A-B ).…”

Section: Resultsmentioning

confidence: 99%

“…FMRP directly associates with polyribosomes in ribonucleoprotein particles (RNPs) and binds over 1000 different mRNA species in brain (Ascano et al, 2012; Bagni & Zukin, 2019; V. Brown et al, 2001; Darnell et al, 2011; Darnell & Klann, 2013; Hale et al, 2021; Sawicka et al, 2019). Its target mRNAs are necessary for long-term plasticity and are predominately synaptic with critical functions in neurotransmission (Bagni & Zukin, 2019; Chyung et al, 2018; Darnell et al, 2011; Hale et al, 2021; Monday et al, 2022b; Sawicka et al, 2019). Evidence in brain circuits shows that axonal translation occurs near boutons and that FMRP regulates this process to modify long-term presynaptic function (Christie et al, 2009; Hafner et al, 2019; Monday et al, 2022b; Scarnati et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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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: Resultssupporting

confidence: 84%

Section: Resultssupporting

confidence: 74%

Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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Synaptopodin regulates denervation-induced plasticity at hippocampal mossy fiber synapses

Kruse

Vlachos

Lenz

2022

Preprint

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Neurological diseases can lead to the denervation of brain regions caused by demyelination, traumatic injury or cell death. Nevertheless, the molecular and structural mechanisms underlying the lesion-induced reorganization of denervated brain regions are a matter of ongoing investigation. In order to address this issue, we performed an entorhinal cortex lesion (ECL) in organotypic entorhinal-hippocampal tissue cultures and studied denervation-induced homeostatic plasticity of mossy fiber synapses, which connect dentate granule cells with CA3 pyramidal neurons and play important roles in spatial learning. Partial denervation caused a homeostatic strengthening of excitatory neurotransmission in dentate granule cells (GC), in CA3 pyramidal neurons, and their direct synaptic connections as revealed by paired recordings (GC-to-CA3). These functional changes were accompanied by ultrastructural reorganization of mossy fiber synapses, which regularly contain the plasticity-related protein synaptopodin and the spine apparatus organelle. We demonstrate that the spine apparatus organelle and its associated protein synaptopodin assemble ribosomes in close proximity to synaptic sites and moreover we unravel synaptopodin-related transcriptome, which can be linked to the expression of homeostatic synaptic plasticity. Notably, synaptopodin-deficient tissue preparations that lack the spine apparatus organelle, failed to express homeostatic adjustments of both excitatory neurotransmission and the region-specific transcriptome. Hence, synaptopodin and the spine apparatus organelle form local protein synthesis hubs that are essential for mediating lesion-induced homeostatic synaptic plasticity.

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Presynaptic FMRP and Local Protein Synthesis Support Structural and Functional Plasticity of Glutamatergic Axon Terminals

Cited by 2 publications

References 74 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

Synaptopodin regulates denervation-induced plasticity at hippocampal mossy fiber synapses

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