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Article ; Online: I

Vasylyev, Dmytro V / Liu, Shujun / Waxman, Stephen G

2023 Volume 601, Issue 23, Page(s) 5341–5366

Abstract: We show here that hyperpolarization-activated current ( ... ...

Abstract	We show here that hyperpolarization-activated current (I
MeSH term(s)	Animals ; Humans ; Erythromelalgia/genetics ; Nociceptors ; Rodentia ; Ganglia, Spinal/physiology ; NAV1.7 Voltage-Gated Sodium Channel/genetics ; Neuralgia/genetics ; Neurons/physiology ; Action Potentials
Chemical Substances	NAV1.7 Voltage-Gated Sodium Channel
Language	English
Publishing date	2023-10-17
Publishing country	England
Document type	Journal Article
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/JP284999
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Article ; Online: Longer looks for language: Novel labels lengthen fixation duration for 2-year-old children.

LaTourrette, Alexander S / Novack, Miriam A / Waxman, Sandra R

Journal of experimental child psychology

2023 Volume 236, Page(s) 105754

Abstract: ... object (e.g., "Look at the dax") compared with when they hear a non-labeling phrase (e.g., "Look ...

Abstract	The language infants hear guides their visual attention; infants look more to objects when they are labeled. However, it is unclear whether labels also change the way infants attend to and encode those objects-that is, whether hearing an object label changes infants' online visual processing of that object. Here, we examined this question in the context of novel word learning, asking whether nuanced measures of visual attention, specifically fixation durations, change when 2-year-olds hear a label for a novel object (e.g., "Look at the dax") compared with when they hear a non-labeling phrase (e.g., "Look at that"). Results confirmed that children visually process objects differently when they are labeled, using longer fixations to examine labeled objects versus unlabeled objects. Children also showed robust retention of these labels on a subsequent test trial, suggesting that these longer fixations accompanied successful word learning. Moreover, when children were presented with the same objects again in a silent re-exposure phase, children's fixations were again longer when looking at the previously labeled objects. Finally, fixation duration at first exposure and silent re-exposure were correlated, indicating a persistent effect of language on visual processing. These effects of hearing labels on visual attention point to the critical interactions involved in cross-modal learning and emphasize the benefits of looking beyond aggregate measures of attention to identify cognitive learning mechanisms during infancy.
MeSH term(s)	Infant ; Humans ; Child, Preschool ; Language ; Learning ; Verbal Learning ; Visual Perception ; Language Development
Language	English
Publishing date	2023-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218137-x
ISSN	1096-0457 ; 0022-0965
ISSN (online)	1096-0457
ISSN	0022-0965
DOI	10.1016/j.jecp.2023.105754
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Article: Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability.

Estacion, Mark / Liu, Shujun / Cheng, Xiaoyang / Dib-Hajj, Sulayman / Waxman, Stephen G

Frontiers in pharmacology

2023 Volume 14, Page(s) 1138556

Abstract: Chronic pain is highly prevalent and remains a significant unmet global medical need. As part of a search for modulatory genes that confer pain resilience, we have studied two family cohorts where one individual reported much less pain than other family ... ...

Abstract	Chronic pain is highly prevalent and remains a significant unmet global medical need. As part of a search for modulatory genes that confer pain resilience, we have studied two family cohorts where one individual reported much less pain than other family members that share the same pathogenic gain-of-function Nav1.7 mutation that confers hyperexcitability on pain-signaling dorsal root ganglion (DRG) neurons. In each of these kindreds, the pain-resilient individual carried a gain-of-function variant in Kv7.2 or Kv7.3, two potassium channels that stabilize membrane potential and reduce excitability. Our observation in this molecular genetic study that these gain-of-function Kv7.2 and 7.3 variants reduce DRG neuron excitability suggests that agents that activate or open Kv7 channels should attenuate sensory neuron firing. In the present study, we assess the effects on sensory neuron excitability of three Kv7 modulators-retigabine (Kv7.2 thru Kv7.5 activator), ICA-110381 (Kv7.2/Kv7.3 specific activator), and as a comparator ML277 (Kv7.1 specific activator)-in a "human-pain-in-a-dish" model (human iPSC-derived sensory neurons, iPSC-SN). Multi-electrode-array (MEA) recordings demonstrated inhibition of firing with retigabine and ICA-110381 (but not with ML277), with the concentration-response curve indicating that retigabine can achieve a 50% reduction of firing with sub-micromolar concentrations. Current-clamp recording demonstrated that retigabine hyperpolarized iPSC-SN resting potential and increased threshold. This study implicates Kv7.2/Kv7.3 channels as effective modulators of sensory neuron excitability, and suggest that compounds that specifically target Kv7.2/Kv7.3 currents in sensory neurons, including human sensory neurons, might provide an effective approach toward pain relief.
Language	English
Publishing date	2023-02-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2023.1138556
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Article ; Online: Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol.

Ghovanloo, Mohammad-Reza / Effraim, Philip R / Tyagi, Sidharth / Zhao, Peng / Dib-Hajj, Sulayman D / Waxman, Stephen G

Communications biology

2024 Volume 7, Issue 1, Page(s) 120

Abstract: Cannabinol (CBN), an incompletely understood metabolite for ∆9-tetrahydrocannabinol, has been suggested as an analgesic. CBN interacts with endocannabinoid (CB) receptors, but is also reported to interact with non-CB targets, including various ion ... ...

Abstract	Cannabinol (CBN), an incompletely understood metabolite for ∆9-tetrahydrocannabinol, has been suggested as an analgesic. CBN interacts with endocannabinoid (CB) receptors, but is also reported to interact with non-CB targets, including various ion channels. We assessed CBN effects on voltage-dependent sodium (Nav) channels expressed heterologously and in native dorsal root ganglion (DRG) neurons. Our results indicate that CBN is a functionally-selective, but structurally-non-selective Nav current inhibitor. CBN's main effect is on slow inactivation. CBN slows recovery from slow-inactivated states, and hyperpolarizes steady-state inactivation, as channels enter deeper and slower inactivated states. Multielectrode array recordings indicate that CBN attenuates DRG neuron excitability. Voltage- and current-clamp analysis of freshly isolated DRG neurons via our automated patch-clamp platform confirmed these findings. The inhibitory effects of CBN on Nav currents and on DRG neuron excitability add a new dimension to its actions and suggest that this cannabinoid may be useful for neuropathic pain.
MeSH term(s)	Cannabinol ; Ganglia, Spinal ; Dronabinol ; Inhibition, Psychological ; Neurons
Chemical Substances	Cannabinol (7UYP6MC9GH) ; Dronabinol (7J8897W37S)
Language	English
Publishing date	2024-01-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-024-05781-x
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Article ; Online: Conditional Astrocyte Rac1KO Attenuates Hyperreflexia after Spinal Cord Injury.

Benson, Curtis A / Olson, Kai-Lan / Patwa, Siraj / Kauer, Sierra D / King, Jared F / Waxman, Stephen G / Tan, Andrew M

The Journal of neuroscience : the official journal of the Society for Neuroscience

2024 Volume 44, Issue 1

Abstract: Spasticity is a hyperexcitability disorder that adversely impacts functional recovery and rehabilitative efforts after spinal cord injury (SCI). The loss of evoked rate-dependent depression (RDD) of the monosynaptic H-reflex is indicative of ... ...

Abstract	Spasticity is a hyperexcitability disorder that adversely impacts functional recovery and rehabilitative efforts after spinal cord injury (SCI). The loss of evoked rate-dependent depression (RDD) of the monosynaptic H-reflex is indicative of hyperreflexia, a physiological sign of spasticity. Given the intimate relationship between astrocytes and neurons, that is, the tripartite synapse, we hypothesized that astrocytes might have a significant role in post-injury hyperreflexia and plasticity of neighboring neuronal synaptic dendritic spines. Here, we investigated the effect of selective Rac1KO in astrocytes (i.e., adult male and female mice, transgenic cre-flox system) on SCI-induced spasticity. Three weeks after a mild contusion SCI, control Rac1
MeSH term(s)	Mice ; Male ; Female ; Animals ; Reflex, Abnormal ; Astrocytes/metabolism ; Spinal Cord Injuries ; Motor Neurons/physiology ; Spinal Cord/metabolism ; Animals, Genetically Modified ; H-Reflex ; Amino Acid Transport System X-AG/metabolism
Chemical Substances	Amino Acid Transport System X-AG
Language	English
Publishing date	2024-01-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.1670-22.2023
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Article ; Online: Nav1.7 P610T mutation in two siblings with persistent ocular pain after corneal axon transection: impaired slow inactivation and hyperexcitable trigeminal neurons.

Ghovanloo, Mohammad-Reza / Effraim, Philip R / Yuan, Jun-Hui / Schulman, Betsy R / Jacobs, Deborah S / Dib-Hajj, Sulayman D / Waxman, Stephen G

Journal of neurophysiology

2023 Volume 129, Issue 3, Page(s) 609–618

Abstract: Despite extensive study, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain after corneal refractive surgery provides a model, in humans, of the effect of injury to trigeminal afferent nerves. Axons of trigeminal ... ...

Abstract	Despite extensive study, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain after corneal refractive surgery provides a model, in humans, of the effect of injury to trigeminal afferent nerves. Axons of trigeminal ganglion neurons that innervate the cornea are transected by laser-assisted in situ keratomileusis (LASIK). Although most patients do not experience postoperative pain, a small subgroup develop persistent ocular pain. We previously carried out genomic analysis and determined that some patients with persistent pain after axotomy of corneal axons during refractive surgery carry mutations in genes that encode the electrogenisome of trigeminal ganglion neurons, the ensemble of ion channels and receptors that regulate excitability within these cells, including
MeSH term(s)	Humans ; Male ; Axons ; Cornea ; Eye Pain ; Ganglia, Spinal ; Mutation ; NAV1.7 Voltage-Gated Sodium Channel/genetics ; Neurons/physiology ; Pain ; Siblings
Chemical Substances	NAV1.7 Voltage-Gated Sodium Channel ; SCN9A protein, human
Language	English
Publishing date	2023-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	80161-6
ISSN	1522-1598 ; 0022-3077
ISSN (online)	1522-1598
ISSN	0022-3077
DOI	10.1152/jn.00457.2022
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Article: Does Human Touch Facilitate Object Categorization in 6-to-9-Month-Old Infants?

Kadlaskar, Girija / Waxman, Sandra / Seidl, Amanda

Brain sciences

2020 Volume 10, Issue 12

Abstract: Infants form object categories in the first months of life. By 3 months and throughout the first year, successful categorization varies as a function of the acoustic information presented in conjunction with category members. Here we ask whether tactile ... ...

Abstract	Infants form object categories in the first months of life. By 3 months and throughout the first year, successful categorization varies as a function of the acoustic information presented in conjunction with category members. Here we ask whether tactile information, delivered in conjunction with category members, also promotes categorization. Six- to 9-month-olds participated in an object categorization task in either a touch-cue or no-cue condition. For infants in the touch-cue condition, familiarization images were accompanied by precisely-timed light touches from their caregivers; infants in the no-cue condition saw the same images but received no touches. Only infants in the touch-cue condition formed categories. This provides the first evidence that touch may play a role in supporting infants' object categorization.
Language	English
Publishing date	2020-12-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci10120940
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Article ; Online: Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability.

Alsaloum, Matthew / Labau, Julie I R / Liu, Shujun / Effraim, Philip R / Waxman, Stephen G

Brain : a journal of neurology

2022 Volume 146, Issue 1, Page(s) 359–371

Abstract: Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of NaV1.7-selective blockers have shown ...

Abstract	Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of NaV1.7-selective blockers have shown limited success and translation to clinical studies has been limited. The degree of NaV1.7 channel blockade necessary to attenuate neuronal excitability and ameliorate pain is an unanswered question important for drug discovery. Here, we utilize dynamic clamp electrophysiology and induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) to answer this question for inherited erythromelalgia, a pain disorder caused by gain-of-function mutations in Nav1.7. We show that dynamic clamp can produce hyperexcitability in iPSC-SNs associated with two different inherited erythromelalgia mutations, NaV1.7-S241T and NaV1.7-I848T. We further show that blockade of approximately 50% of NaV1.7 currents can reverse neuronal hyperexcitability to baseline levels.
MeSH term(s)	Humans ; Erythromelalgia/genetics ; Erythromelalgia/drug therapy ; NAV1.7 Voltage-Gated Sodium Channel/genetics ; Mutation/genetics ; Pain ; Sensory Receptor Cells ; Ganglia, Spinal
Chemical Substances	NAV1.7 Voltage-Gated Sodium Channel
Language	English
Publishing date	2022-01-26
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awac031
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Article ; Online: Ccdc103 promotes myeloid cell proliferation and migration independent of motile cilia.

Falkenberg, Lauren G / Beckman, Sarah A / Ravisankar, Padmapriyadarshini / Dohn, Tracy E / Waxman, Joshua S

Disease models & mechanisms

2021 Volume 14, Issue 5

Abstract: The pathology of primary ciliary dyskinesia (PCD) is predominantly attributed to impairment of motile cilia. However, PCD patients also have perplexing functional defects in myeloid cells, which lack motile cilia. Here, we show that coiled-coil domain- ... ...

Abstract	The pathology of primary ciliary dyskinesia (PCD) is predominantly attributed to impairment of motile cilia. However, PCD patients also have perplexing functional defects in myeloid cells, which lack motile cilia. Here, we show that coiled-coil domain-containing protein 103 (CCDC103), one of the genes that, when mutated, is known to cause PCD, is required for the proliferation and directed migration of myeloid cells. CCDC103 is expressed in human myeloid cells, where it colocalizes with cytoplasmic microtubules. Zebrafish ccdc103/schmalhans (smh) mutants have macrophages and neutrophils with reduced proliferation, abnormally rounded cell morphology and an inability to migrate efficiently to the site of sterile wounds, all of which are consistent with a loss of cytoplasmic microtubule stability. Furthermore, we demonstrate that direct interactions between CCDC103 and sperm associated antigen 6 (SPAG6), which also promotes microtubule stability, are abrogated by CCDC103 mutations from PCD patients, and that spag6 zebrafish mutants recapitulate the myeloid defects observed in smh mutants. In summary, we have illuminated a mechanism, independent of motile cilia, to explain functional defects in myeloid cells from PCD patients. This article has an associated First Person interview with the first author of the paper.
MeSH term(s)	Animals ; Humans ; Cell Movement ; Cell Proliferation ; Cilia/metabolism ; Embryo, Nonmammalian/metabolism ; Green Fluorescent Proteins/metabolism ; HEK293 Cells ; HL-60 Cells ; Microtubules/metabolism ; Mutation/genetics ; Myeloid Cells/cytology ; Myeloid Cells/metabolism ; Neutrophils/metabolism ; Protein Binding ; Stem Cells/metabolism ; Zebrafish/embryology ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
Chemical Substances	Green Fluorescent Proteins (147336-22-9) ; Zebrafish Proteins ; Ccdc103 protein, zebrafish
Language	English
Publishing date	2021-05-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.048439
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Article: Conserved but not critical: Trafficking and function of Na

Tyagi, Sidharth / Sarveswaran, Nivedita / Higerd-Rusli, Grant P / Liu, Shujun / Dib-Hajj, Fadia B / Waxman, Stephen G / Dib-Hajj, Sulayman D

Frontiers in molecular neuroscience

2023 Volume 16, Page(s) 1161028

Abstract: Non-addictive treatment of chronic pain represents a major unmet clinical need. Peripheral voltage-gated sodium ( ... ...

Abstract	Non-addictive treatment of chronic pain represents a major unmet clinical need. Peripheral voltage-gated sodium (Na
Language	English
Publishing date	2023-03-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2023.1161028
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