scholarly journals Sustained Loss of Bdnf Affects Peripheral but Not Central Vestibular Targets

2021 ◽  
Vol 12 ◽  
Author(s):  
Karen L. Elliott ◽  
Jennifer Kersigo ◽  
Jeong Han Lee ◽  
Ebenezer N. Yamoah ◽  
Bernd Fritzsch
Keyword(s):  
Vestibular System ◽  
Hair Cells ◽  
Molecular Mechanisms ◽  
Vestibular Nucleus ◽  
Target Cells ◽  
Central Target ◽  
Vestibular Ganglion ◽  
Vestibular Hair Cells ◽  
Ganglion Neurons

The vestibular system is vital for proper balance perception, and its dysfunction contributes significantly to fall-related injuries, especially in the elderly. Vestibular ganglion neurons innervate vestibular hair cells at the periphery and vestibular nuclei and the uvula and nodule of the cerebellum centrally. During aging, these vestibular ganglion neurons degenerate, impairing vestibular function. A complete understanding of the molecular mechanisms involved in neurosensory cell survival in the vestibular system is unknown. Brain-derived neurotrophic factor (BDNF) is specifically required for the survival of vestibular ganglion neurons, as its loss leads to early neuronal death. Bdnf null mice die within 3 weeks of birth, preventing the study of the long-term effects on target cells. We use Pax2-cre to conditionally knock out Bdnf, allowing mice survival to approximately 6 months of age. We show that a long-term loss of Bdnf leads to a significant reduction in the number of vestibular ganglion neurons and a reduction in the number of vestibular hair cells. There was no significant decrease in the central targets lateral vestibular nucleus (LVN) or the cerebellum at 6 months. This suggests that the connectivity between central target cells and other neurons suffices to prevent their loss despite vestibular hair cell and ganglion neuron loss. Whether the central neurons would undergo eventual degeneration in the absence of Bdnf remains to be determined.

Morphological and morphometric characteristics of vestibular hair cells and support cells in long term cultures of rat utricle explants

2012 ◽  
Vol 283 (1-2) ◽  
pp. 107-116 ◽  
Author(s):  
Mimmi Werner ◽  
Thomas R. Van De Water ◽  
Therese Andersson ◽  
Göran Arnoldsson ◽  
Diana Berggren
Keyword(s):  
Hair Cells ◽  
Morphometric Characteristics ◽  
Vestibular Hair Cells

scholarly journals Mechanotransduction and hyperpolarization-activated currents contribute to spontaneous activity in mouse vestibular ganglion neurons

2014 ◽  
Vol 143 (4) ◽  
pp. 481-497 ◽  
Author(s):  
Geoffrey C. Horwitz ◽  
Jessica R. Risner-Janiczek ◽  
Jeffrey R. Holt
Keyword(s):  
Hair Cell ◽  
Spontaneous Activity ◽  
Action Potentials ◽  
Ex Vivo ◽  
Vestibular Neuron ◽  
Vestibular Ganglion ◽  
Vestibular Hair Cells ◽  
Reverse Transcription Pcr ◽  
Current Clamp Mode ◽  
Ganglion Neurons

The hyperpolarization-activated, cyclic nucleotide–sensitive current, Ih, is present in vestibular hair cells and vestibular ganglion neurons, and is required for normal balance function. We sought to identify the molecular correlates and functional relevance of Ih in vestibular ganglion neurons. Ih is carried by channels consisting of homo- or heteromeric assemblies of four protein subunits from the Hcn gene family. The relative expression of Hcn1–4 mRNA was examined using a quantitative reverse transcription PCR (RT-PCR) screen. Hcn2 was the most highly expressed subunit in vestibular neuron cell bodies. Immunolocalization of HCN2 revealed robust expression in cell bodies of all vestibular ganglion neurons. To characterize Ih in vestibular neuron cell bodies and at hair cell–afferent synapses, we developed an intact, ex vivo preparation. We found robust physiological expression of Ih in 89% of cell bodies and 100% of calyx terminals. Ih was significantly larger in calyx terminals than in cell bodies; however, other biophysical characteristics were similar. Ih was absent in calyces lacking Hcn1 and Hcn2, but small Ih was still present in cell bodies, which suggests expression of an additional subunit, perhaps Hcn4. To determine the contributions of hair cell mechanotransduction and Ih to the firing patterns of calyx terminals, we recorded action potentials in current-clamp mode. Mechanotransduction currents were modulated by hair bundle defection and application of calcium chelators to disrupt tip links. Ih activity was modulated using ZD7288 and cAMP. We found that both hair cell transduction and Ih contribute to the rate and regularity of spontaneous action potentials in the vestibular afferent neurons. We propose that modulation of Ih in vestibular ganglion neurons may provide a mechanism for modulation of spontaneous activity in the vestibular periphery.

scholarly journals Chronic Lead Exposure Results in Auditory Deficits and Disruption of Hair Cells in Postweaning Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Shou-Sen Hu ◽  
Shi-Zhong Cai ◽  
Xiang-Zhen Kong
Keyword(s):  
Lead Exposure ◽  
Hair Cells ◽  
Molecular Mechanisms ◽  
Basilar Membrane ◽  
Morphological Changes ◽  
Spiral Ganglion ◽  
Antioxidant Enzyme Activities ◽  
Auditory Evoked Responses ◽  
Catalytic Function ◽  
Ganglion Neurons

Objective. The effects of lead exposure on cognitive function have been studied intensively over the past decade, but less attention has focused on its impact on auditory function. This study is aimed at investigating the effect of lead on the cochlea and the molecular mechanisms responsible for its actions. Methods. 0.2% lead acetate was administered to rats in drinking water for 30, 60, and 90 days. Brainstem auditory evoked responses (ABR) were recorded, and morphological changes in the hair cells were observed. We also measured glutathione (GSH) and malondialdehyde (MDA) concentrations and antioxidant enzyme activities such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activities in the cochlea. Results. Lead exposure increased the ABR threshold and slightly prolonged the latencies of wave II and wave IV in rats. Abnormally shaped hair cells and loss of hair cells were found in the cochlea basilar membrane, together with degenerative changes in spiral ganglion neurons following lead exposure. The activities of some antioxidant enzymes were also reduced in association with upregulation of MDA expression. These effects may be caused by impaired catalytic function of the enzymes as a result of lead interaction. Conclusion. The antioxidant system of the cochlea in the immature rat brain is highly vulnerable to developmental lead exposure. Oxidative stress may therefore represent a possible mechanism for lead-induced auditory deficits.

scholarly journals ACh-induced hyperpolarization and decreased resistance in mammalian type II vestibular hair cells

2018 ◽  
Vol 119 (1) ◽  
pp. 312-325 ◽  
Author(s):  
Lauren A. Poppi ◽  
Hessam Tabatabaee ◽  
Hannah R. Drury ◽  
Phillip Jobling ◽  
Robert J. Callister ◽  
...  
Keyword(s):  
Hair Cell ◽  
Vestibular System ◽  
Hair Cells ◽  
Outward Current ◽  
Membrane Resistance ◽  
Type Ii ◽  
Sk Channels ◽  
Cellular Mechanisms ◽  
Membrane Hyperpolarization ◽  
Vestibular Hair Cells

In the mammalian vestibular periphery, electrical activation of the efferent vestibular system (EVS) has two effects on afferent activity: 1) it increases background afferent discharge and 2) decreases afferent sensitivity to rotational stimuli. Although the cellular mechanisms underlying these two contrasting afferent responses remain obscure, we postulated that the reduction in afferent sensitivity was attributed, in part, to the activation of α9- containing nicotinic acetylcholine (ACh) receptors (α9*nAChRs) and small-conductance potassium channels (SK) in vestibular type II hair cells, as demonstrated in the peripheral vestibular system of other vertebrates. To test this hypothesis, we examined the effects of the predominant EVS neurotransmitter ACh on vestibular type II hair cells from wild-type (wt) and α9-subunit nAChR knockout (α9−/−) mice. Immunostaining for choline acetyltransferase revealed there were no obvious gross morphological differences in the peripheral EVS innervation among any of these strains. ACh application onto wt type II hair cells, at resting potentials, produced a fast inward current followed by a slower outward current, resulting in membrane hyperpolarization and decreased membrane resistance. Hyperpolarization and decreased resistance were due to gating of SK channels. Consistent with activation of α9*nAChRs and SK channels, these ACh-sensitive currents were antagonized by the α9*nAChR blocker strychnine and SK blockers apamin and tamapin. Type II hair cells from α9−/− mice, however, failed to respond to ACh at all. These results confirm the critical importance of α9nAChRs in efferent modulation of mammalian type II vestibular hair cells. Application of exogenous ACh reduces electrical impedance, thereby decreasing type II hair cell sensitivity. NEW & NOTEWORTHY Expression of α9 nicotinic subunit was crucial for fast cholinergic modulation of mammalian vestibular type II hair cells. These findings show a multifaceted efferent mechanism for altering hair cell membrane potential and decreasing membrane resistance that should reduce sensitivity to hair bundle displacements.

scholarly journals Heat pulse excitability of vestibular hair cells and afferent neurons

2016 ◽  
Vol 116 (2) ◽  
pp. 825-843 ◽  
Author(s):  
Richard D. Rabbitt ◽  
Alan M. Brichta ◽  
Hessam Tabatabaee ◽  
Peter J. Boutros ◽  
JoongHo Ahn ◽  
...  
Keyword(s):  
Hair Cells ◽  
Quantitative Methods ◽  
Heat Pulse ◽  
Membrane Currents ◽  
Afferent Neurons ◽  
Conduction Current ◽  
Whole Cell ◽  
Vestibular Hair Cells ◽  
Heat Pulses ◽  
Ganglion Neurons

In the present study we combined electrophysiology with optical heat pulse stimuli to examine thermodynamics of membrane electrical excitability in mammalian vestibular hair cells and afferent neurons. We recorded whole cell currents in mammalian type II vestibular hair cells using an excised preparation (mouse) and action potentials (APs) in afferent neurons in vivo (chinchilla) in response to optical heat pulses applied to the crista (Δ T ≈ 0.25°C per pulse). Afferent spike trains evoked by heat pulse stimuli were diverse and included asynchronous inhibition, asynchronous excitation, and/or phase-locked APs synchronized to each infrared heat pulse. Thermal responses of membrane currents responsible for APs in ganglion neurons were strictly excitatory, with Q10 ≈ 2. In contrast, hair cells responded with a mix of excitatory and inhibitory currents. Excitatory hair cell membrane currents included a thermoelectric capacitive current proportional to the rate of temperature rise (d T/d t) and an inward conduction current driven by Δ T. An iberiotoxin-sensitive inhibitory conduction current was also evoked by Δ T, rising in <3 ms and decaying with a time constant of ∼24 ms. The inhibitory component dominated whole cell currents in 50% of hair cells at −68 mV and in 67% of hair cells at −60 mV. Responses were quantified and described on the basis of first principles of thermodynamics. Results identify key molecular targets underlying heat pulse excitability in vestibular sensory organs and provide quantitative methods for rational application of optical heat pulses to examine protein biophysics and manipulate cellular excitability.

scholarly journals The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1828
Author(s):  
Jared Kirui ◽  
Yara Abidine ◽  
Annasara Lenman ◽  
Koushikul Islam ◽  
Yong-Dae Gwon ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Molecular Mechanisms ◽  
Rna Virus ◽  
Ectopic Expression ◽  
Point Mutations ◽  
Cell Entry ◽  
Target Cells ◽  
Human Hepatoma Cells ◽  
Chikv Infection ◽  
Phosphatidylserine Receptor

Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain poorly understood. The phosphatidylserine-dependent receptors, T-cell immunoglobulin and mucin domain 1 (TIM-1) and Axl receptor tyrosine kinase (Axl), are transmembrane proteins that can serve as entry factors for enveloped viruses. Previous studies used pseudoviruses to delineate the role of TIM-1 and Axl in CHIKV entry. Conversely, here, we use the authentic CHIKV and cells ectopically expressing TIM-1 or Axl and demonstrate a role for TIM-1 in CHIKV infection. To further characterize TIM-1-dependent CHIKV infection, we generated cells expressing domain mutants of TIM-1. We show that point mutations in the phosphatidylserine binding site of TIM-1 lead to reduced binding, entry, and infection of CHIKV. Ectopic expression of TIM-1 renders immortalized keratinocytes permissive to CHIKV, whereas silencing of endogenously expressed TIM-1 in human hepatoma cells reduces CHIKV infection. Altogether, our findings indicate that, unlike Axl, TIM-1 readily promotes the productive entry of authentic CHIKV into target cells.

scholarly journals Cardiac Cell Therapy: Insights into the Mechanisms of Tissue Repair

2021 ◽  
Vol 22 (3) ◽  
pp. 1201
Author(s):  
Hsuan Peng ◽  
Kazuhiro Shindo ◽  
Renée R. Donahue ◽  
Ahmed Abdel-Latif
Keyword(s):  
Stem Cell ◽  
Immune Responses ◽  
Tissue Repair ◽  
Molecular Mechanisms ◽  
Clinical Evidence ◽  
Current Knowledge ◽  
Cell Delivery ◽  
Cardiac Cell Therapy ◽  
Stem Cell Treatment

Stem cell-based cardiac therapies have been extensively studied in recent years. However, the efficacy of cell delivery, engraftment, and differentiation post-transplant remain continuous challenges and represent opportunities to further refine our current strategies. Despite limited long-term cardiac retention, stem cell treatment leads to sustained cardiac benefit following myocardial infarction (MI). This review summarizes the current knowledge on stem cell based cardiac immunomodulation by highlighting the cellular and molecular mechanisms of different immune responses to mesenchymal stem cells (MSCs) and their secretory factors. This review also addresses the clinical evidence in the field.

Sign in / Sign up

Export Citation Format

Share Document