Hyperexcitability of Sensory Neurons in Fragile X Mouse Model

Sensory hypersensitivity and somatosensory deficits represent the core symptoms of Fragile X syndrome (FXS). These alterations are believed to arise from changes in cortical sensory processing, while potential deficits in the function of peripheral sensory neurons residing in dorsal root ganglia remain unexplored. We found that peripheral sensory neurons exhibit pronounced hyperexcitability in Fmr1 KO mice, manifested by markedly increased action potential (AP) firing rate and decreased threshold. Unlike excitability changes found in many central neurons, no significant changes were observed in AP rising and falling time, peak potential, amplitude, or duration. Sensory neuron hyperexcitability was caused primarily by increased input resistance, without changes in cell capacitance or resting membrane potential. Analyses of the underlying mechanisms revealed reduced activity of HCN channels and reduced expression of HCN1 and HCN4 in Fmr1 KO compared to WT. A selective HCN channel blocker abolished differences in all measures of sensory neuron excitability between WT and Fmr1 KO neurons. These results reveal a hyperexcitable state of peripheral sensory neurons in Fmr1 KO mice caused by dysfunction of HCN channels. In addition to the intrinsic neuronal dysfunction, the accompanying paper examines deficits in sensory neuron association/communication with their enveloping satellite glial cells, suggesting contributions from both neuronal intrinsic and extrinsic mechanisms to sensory dysfunction in the FXS mouse model.

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Disrupted Association of Sensory Neurons With Enveloping Satellite Glial Cells in Fragile X Mouse Model

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.796070 ◽

2022 ◽

Vol 14 ◽

Author(s):

Oshri Avraham ◽

Pan-Yue Deng ◽

Dario Maschi ◽

Vitaly A. Klyachko ◽

Valeria Cavalli

Keyword(s):

Sensory Neuron ◽

Glial Cells ◽

Fragile X ◽

Sensory System ◽

Structural Defects ◽

Learning Networks ◽

Sensory Stimuli ◽

Satellite Glial Cells ◽

Sensory Deficits ◽

Peripheral Sensory

Among most prevalent deficits in individuals with Fragile X syndrome (FXS) is hypersensitivity to sensory stimuli and somatosensory alterations. Whether dysfunction in peripheral sensory system contributes to these deficits remains poorly understood. Satellite glial cells (SGCs), which envelop sensory neuron soma, play critical roles in regulating neuronal function and excitability. The potential contributions of SGCs to sensory deficits in FXS remain unexplored. Here we found major structural defects in sensory neuron-SGC association in the dorsal root ganglia (DRG), manifested by aberrant covering of the neuron and gaps between SGCs and the neuron along their contact surface. Single-cell RNAseq analyses demonstrated transcriptional changes in both neurons and SGCs, indicative of defects in neuronal maturation and altered SGC vesicular secretion. We validated these changes using fluorescence microscopy, qPCR, and high-resolution transmission electron microscopy (TEM) in combination with computational analyses using deep learning networks. These results revealed a disrupted neuron-glia association at the structural and functional levels. Given the well-established role for SGCs in regulating sensory neuron function, altered neuron-glia association may contribute to sensory deficits in FXS.

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Correction to “Regulation of d Opioid Receptor-Mediated Signaling and Antinociception in Peripheral Sensory Neurons by Arachidonic Acid–Dependent 12/15-Lipoxygenase Metabolites”

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.112.241604err ◽

2019 ◽

Vol 369 (1) ◽

pp. 143-143

Keyword(s):

Arachidonic Acid ◽

Opioid Receptor ◽

Sensory Neurons ◽

Peripheral Sensory Neurons ◽

Peripheral Sensory

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Modulation of μ-opioid receptor desensitization in peripheral sensory neurons by phosphoinositide 3-kinase γ

Neuroscience ◽

10.1016/j.neuroscience.2010.04.068 ◽

2010 ◽

Vol 169 (1) ◽

pp. 449-454 ◽

Cited By ~ 15

Author(s):

C. König ◽

O. Gavrilova-Ruch ◽

G. Segond von Banchet ◽

R. Bauer ◽

M. Grün ◽

...

Keyword(s):

Opioid Receptor ◽

Sensory Neurons ◽

Receptor Desensitization ◽

Peripheral Sensory Neurons ◽

Μ Opioid Receptor ◽

Phosphoinositide 3 Kinase ◽

Peripheral Sensory

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A-kinase anchoring protein 79/150 coordinates metabotropic glutamate receptor sensitization of peripheral sensory neurons

Pain ◽

10.1097/j.pain.0000000000000295 ◽

2015 ◽

Vol 156 (11) ◽

pp. 2364-2372 ◽

Cited By ~ 9

Author(s):

Kalina Szteyn ◽

Matthew P. Rowan ◽

Ruben Gomez ◽

Junhui Du ◽

Susan M. Carlton ◽

...

Keyword(s):

Glutamate Receptor ◽

Sensory Neurons ◽

Metabotropic Glutamate Receptor ◽

Metabotropic Glutamate ◽

Peripheral Sensory Neurons ◽

Anchoring Protein ◽

Peripheral Sensory

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Selective Expression of a SNARE-Cleaving Protease in Peripheral Sensory Neurons Attenuates Pain-Related Gene Transcription and Neuropeptide Release

International Journal of Molecular Sciences ◽

10.3390/ijms22168826 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8826

Author(s):

Wanzhi Wang ◽

Miaomiao Kong ◽

Yu Dou ◽

Shanghai Xue ◽

Yang Liu ◽

...

Keyword(s):

Chronic Pain ◽

Sensory Neurons ◽

Transient Receptor Potential ◽

Safety Concern ◽

Unmet Need ◽

Nociceptive Neurons ◽

Neuropeptide Release ◽

Selective Expression ◽

Peripheral Sensory Neurons ◽

Peripheral Sensory

Chronic pain is a leading health and socioeconomic problem and an unmet need exists for long-lasting analgesics. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) are required for neuropeptide release and noxious signal transducer surface trafficking, thus, selective expression of the SNARE-cleaving light-chain protease of botulinum neurotoxin A (LCA) in peripheral sensory neurons could alleviate chronic pain. However, a safety concern to this approach is the lack of a sensory neuronal promoter to prevent the expression of LCA in the central nervous system. Towards this, we exploit the unique characteristics of Pirt (phosphoinositide-interacting regulator of TRP), which is expressed in peripheral nociceptive neurons. For the first time, we identified a Pirt promoter element and cloned it into a lentiviral vector driving transgene expression selectively in peripheral sensory neurons. Pirt promoter driven-LCA expression yielded rapid and concentration-dependent cleavage of SNAP-25 in cultured sensory neurons. Moreover, the transcripts of pain-related genes (TAC1, tachykinin precursor 1; CALCB, calcitonin gene-related peptide 2; HTR3A, 5-hydroxytryptamine receptor 3A; NPY2R, neuropeptide Y receptor Y2; GPR52, G protein-coupled receptor 52; SCN9A, sodium voltage-gated channel alpha subunit 9; TRPV1 and TRPA1, transient receptor potential cation channel subfamily V member 1 and subfamily A member 1) in pro-inflammatory cytokines stimulated sensory neurons were downregulated by viral mediated expression of LCA. Furthermore, viral expression of LCA yielded long-lasting inhibition of pain mediator release. Thus, we show that the engineered Pirt-LCA virus may provide a novel means for long lasting pain relief.

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Aldosterone Synthase in Peripheral Sensory Neurons Contributes to Mechanical Hypersensitivity during Local Inflammation in Rats

Anesthesiology ◽

10.1097/aln.0000000000003127 ◽

2020 ◽

Vol 132 (4) ◽

pp. 867-880 ◽

Cited By ~ 1

Author(s):

Doaa M. Mohamed ◽

Mohammed Shaqura ◽

Xiongjuan Li ◽

Mehdi Shakibaei ◽

Antje Beyer ◽

...

Keyword(s):

Sensory Neurons ◽

Mineralocorticoid Receptor ◽

Mineralocorticoid Receptors ◽

Mineralocorticoid Receptor Antagonist ◽

Aldosterone Synthase ◽

Nociceptive Neurons ◽

Processing Enzyme ◽

Peripheral Sensory Neurons ◽

Synthase Inhibitor ◽

Peripheral Sensory

Abstract Background Recent emerging evidence suggests that extra-adrenal synthesis of aldosterone occurs (e.g., within the failing heart and in certain brain areas). In this study, the authors investigated evidence for a local endogenous aldosterone production through its key processing enzyme aldosterone synthase within peripheral nociceptive neurons. Methods In male Wistar rats (n = 5 to 8 per group) with Freund’s complete adjuvant hind paw inflammation, the authors examined aldosterone, aldosterone synthase, and mineralocorticoid receptor expression in peripheral sensory neurons using quantitative reverse transcriptase–polymerase chain reaction, Western blot, immunohistochemistry, and immunoprecipitation. Moreover, the authors explored the nociceptive behavioral changes after selective mineralocorticoid receptor antagonist, canrenoate-K, or specific aldosterone synthase inhibitor application. Results In rats with Freund’s complete adjuvant–induced hind paw inflammation subcutaneous and intrathecal application of mineralocorticoid receptor antagonist, canrenoate-K, rapidly and dose-dependently attenuated nociceptive behavior (94 and 48% reduction in mean paw pressure thresholds, respectively), suggesting a tonic activation of neuronal mineralocorticoid receptors by an endogenous ligand. Indeed, aldosterone immunoreactivity was abundant in peptidergic nociceptive neurons of dorsal root ganglia and colocalized predominantly with its processing enzyme aldosterone synthase and mineralocorticoid receptors. Moreover, aldosterone and its synthesizing enzyme were significantly upregulated in peripheral sensory neurons under inflammatory conditions. The membrane mineralocorticoid receptor consistently coimmunoprecipitated with endogenous aldosterone, confirming a functional link between mineralocorticoid receptors and its endogenous ligand. Importantly, inhibition of endogenous aldosterone production in peripheral sensory neurons by a specific aldosterone synthase inhibitor attenuated nociceptive behavior after hind paw inflammation (a 32% reduction in paw pressure thresholds; inflammation, 47 ± 2 [mean ± SD] vs. inflammation + aldosterone synthase inhibitor, 62 ± 2). Conclusions Local production of aldosterone by its processing enzyme aldosterone synthase within peripheral sensory neurons contributes to ongoing mechanical hypersensitivity during local inflammation via intrinsic activation of neuronal mineralocorticoid receptors. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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Phenotypic and Functional Characterization of Peripheral Sensory Neurons derived from Human Embryonic Stem Cells

Scientific Reports ◽

10.1038/s41598-017-19093-0 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 15

Author(s):

Abdullah Jawad Alshawaf ◽

Serena Viventi ◽

Wanzhi Qiu ◽

Giovanna D’Abaco ◽

Bryony Nayagam ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Sensory Neurons ◽

Human Embryonic Stem Cells ◽

Functional Characterization ◽

Embryonic Stem ◽

Peripheral Sensory Neurons ◽

Peripheral Sensory

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Electrotonic structure of olfactory sensory neurons analyzed by intracellular and whole cell patch techniques

Journal of Neurophysiology ◽

10.1152/jn.1991.65.3.747 ◽

1991 ◽

Vol 65 (3) ◽

pp. 747-758 ◽

Cited By ~ 41

Author(s):

F. Pongracz ◽

S. Firestein ◽

G. M. Shepherd

Keyword(s):

Sensory Neurons ◽

Information Transfer ◽

Experimental Studies ◽

Input Resistance ◽

Resting Membrane Potential ◽

Ambystoma Tigrinum ◽

Olfactory Sensory Neurons ◽

Isolated Cells ◽

Whole Cell

1. Experimental studies employing whole cell patch recordings from freshly isolated olfactory sensory neurons of the salamander (Ambystoma tigrinum) yield much higher estimates of specific membrane resistance (Rm) than studies using conventional intracellular recordings from in situ neurons. Because Rm is critical for understanding information transfer in these cells, we have used computational methods to analyze the possible reasons for this difference. 2. Compartmental models were constructed for both the in situ and isolated neurons, using SABER, a general-purpose simulation program. For Rm in the in situ cell, we used a high value of 100,000 omega.cm2, as estimated in the whole cell recordings from isolated cells. A shunt across the cell membrane caused by the penetrating microelectrode was simulated by several types of shunt mechanisms, and its effects on lowering the apparent value of resting membrane potential (MP), input resistance (RN), and membrane time constant (tau m) and increasing the electrotonic length (L) were analyzed. 3. A good approximation of the electrotonic properties recorded intracellularly was obtained in the in situ model with high Rm combined with an electrode shunt consisting of Na and K conductances. A raised K conductance (1-5 nS) helps to maintain the resting MP while contributing to the increased conductance, which lowers RN and shortens the apparent tau m toward the experimental values. 4. Combined shunt resistances of 0.1-0.2 G omega (5-10 nS) gave the best fits with the experimental data. These shunts were two to three orders of magnitude smaller than the values reported from intracellular penetrations in muscle cells and motoneurons. This may be correlated with the smaller electrode tips used in the recordings from these small neurons. We thus confirm the prediction that even small values of electrode shunt have relatively large effects on the recorded electrotonic properties of small neurons, because of their high RN (2-5 G omega). 5. We have further explored the effects on electrotonic structure of a nonuniform Rm by giving higher Rm values to the distally located cilia compared with the proximal soma-dendritic region, as indicated by recent experiments. For the same RN, large increases in ciliary Rm above 100,000 omega.cm2 can be balanced by relatively small decreases below that value in soma-dendritic Rm. A high ciliary Rm appears to be a specialization for transduction of the sensory input, as reported also in photoreceptors and hair cells.

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