Muscarinic acetylcholine receptors modulate HCN channel properties in vestibular ganglion neurons

Vestibular efferent neurons play an important role in shaping vestibular afferent excitability and accordingly, on the information encoded by their spike patterns. Efferent-modulation is linked to muscarinic signaling cascades that affect ion channel conductances, most notably low-voltage gated potassium channels such as KCNQ. Here we tested and found that muscarinic signaling cascades also modulate hyperpolarization-activated cyclic-nucleotide gated channels (HCN). HCN channels play a key role in controlling spike-timing regularity and a non-chemical form of transmission between type I hair cells and vestibular afferents. The impact of cholinergic efferent input on HCN channels was assessed using voltage-clamp methods, which measure currents in the disassociated cell bodies of vestibular ganglion neurons (VGN). Membrane properties in VGN were characterized before and after administration of the muscarinic acetylcholine receptor (mAChR) agonist Oxotremorine-M (Oxo-M). We found that Oxo-M shifted the voltage-activation range of HCN channels in the positive direction by 4.1 +/- 1.1 mV, which more than doubled the available current when held near rest at -60 mV (a 184 +/- 90.1% increase, n=19). This effect was not blocked by pre-treating the cells with a KCNQ channel blocker, linopirdine, which suggests that this effect is not dependent on KCNQ currents. We also found that HCN channel properties in the baseline condition and sensitivity to mAChR activation depended on cell size and firing patterns. Large-bodied neurons with onset firing patterns had the most depolarized activation range and least sensitivity to mAChR activation. Together, our results highlight the complex and dynamic regulation of HCN channels in VGN.

Sustained Loss of Bdnf Affects Peripheral but Not Central Vestibular Targets

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.

Similarities in the Biophysical Properties of Spiral-Ganglion and Vestibular-Ganglion Neurons in Neonatal Rats

The membranes of auditory and vestibular afferent neurons each contain diverse groups of ion channels that lead to heterogeneity in their intrinsic biophysical properties. Pioneering work in both auditory- and vestibular-ganglion physiology have individually examined this remarkable diversity, but there are few direct comparisons between the two ganglia. Here the firing patterns recorded by whole-cell patch-clamping in neonatal vestibular- and spiral ganglion neurons are compared. Indicative of an overall heterogeneity in ion channel composition, both ganglia exhibit qualitatively similar firing patterns ranging from sustained-spiking to transient-spiking in response to current injection. The range of resting potentials, voltage thresholds, current thresholds, input-resistances, and first-spike latencies are similarly broad in both ganglion groups. The covariance between several biophysical properties (e.g., resting potential to voltage threshold and their dependence on postnatal age) was similar between the two ganglia. Cell sizes were on average larger and more variable in VGN than in SGN. One sub-group of VGN stood out as having extra-large somata with transient-firing patterns, very low-input resistance, fast first-spike latencies, and required large current amplitudes to induce spiking. Despite these differences, the input resistance per unit area of the large-bodied transient neurons was like that of smaller-bodied transient-firing neurons in both VGN and SGN, thus appearing to be size-scaled versions of other transient-firing neurons. Our analysis reveals that although auditory and vestibular afferents serve very different functions in distinct sensory modalities, their biophysical properties are more closely related by firing pattern and cell size than by sensory modality.

Imaging Features Differentiating Vestibular Ganglion from Intracanalicular Schwannoma on Single-Sequence Non-Contrast Magnetic Resonance Imaging Study

Introduction: This study aimed to identify imaging features on single-sequence noncontrast magnetic resonance imaging (MRI) that differentiate the vestibular ganglion from small intracanalicular schwannomas. Materials and Methods: Ninety patients (42 men and 48 women; age: 24‒87 years old) with 102 internal auditory canal (IAC) nodules (59 vestibular ganglia and 43 intracanalicular schwannoma) who underwent both singlesequence T2-weighted (T2W) non-contrast enhanced MRI studies and contrast-enhanced T1-weighted (T1W) MRI studies between May 2012 and April 2017 were evaluated. The length, width, distance to the IAC fundus and length/width ratios for all lesions were obtained and compared among groups. Diagnostic performance and cutoff values of the parameters were evaluated with receiver operating characteristics curve analysis. Area under the curve (AUC) value was calculated. Results: Vestibular ganglia have significantly smaller lengths and widths compared to intracanalicular vestibular schwannomas (1.7 ± 0.4 mm and 1.0 ± 0.2 mm versus 5.6 ± 3.0 mm and 3.7 ± 1.5 mm). They are more fusiform in shape compared to vestibular schwannomas (length/width ratio: 1.8 ± 0.4 versus 1.5 ± 0.4). The lesion width demonstrated the highest diagnostic performance (AUC: 0.998). Using a cutoff width of <1.3 mm, the sensitivity, specificity and overall accuracy for diagnosing vestibular ganglia were 97% (57/59), 100% (43/43) and 98% (100/102), respectively. Conclusion: Vestibular ganglia may mimic intracanalicular vestibular schwannomas on a single-sequence T2W MRI. However, a fusiform shape and width <1.3 mm increases confidence in the diagnosis of ganglia. Identifying the vestibular ganglion on single-sequence T2W MRI studies may obviate the need for a contrast-enhanced MRI, reducing the risks of contrast administration, additional scanning time and cost. Key words: Acoustic neuroma, Internal auditory canal, Vestibulocochlear nerve

A biophysical model examining the role of low-voltage-activated potassium currents in shaping the responses of vestibular ganglion neurons

The vestibular nerve is characterized by two broad groups of neurons that differ in the timing of their interspike intervals; some fire at highly regular intervals, whereas others fire at highly irregular intervals. Heterogeneity in ion channel properties has been proposed as shaping these firing patterns (Highstein SM, Politoff AL. Brain Res 150: 182–187, 1978; Smith CE, Goldberg JM. Biol Cybern 54: 41–51, 1986). Kalluri et al. ( J Neurophysiol 104: 2034–2051, 2010) proposed that regularity is controlled by the density of low-voltage-activated potassium currents ( IKL). To examine the impact of IKL on spike timing regularity, we implemented a single-compartment model with three conductances known to be present in the vestibular ganglion: transient sodium ( gNa), low-voltage-activated potassium ( gKL), and high-voltage-activated potassium ( gKH). Consistent with in vitro observations, removing gKL depolarized resting potential, increased input resistance and membrane time constant, and converted current step-evoked firing patterns from transient (1 spike at current onset) to sustained (many spikes). Modeled neurons were driven with a time-varying synaptic conductance that captured the random arrival times and amplitudes of glutamate-driven synaptic events. In the presence of gKL, spiking occurred only in response to large events with fast onsets. Models without gKL exhibited greater integration by responding to the superposition of rapidly arriving events. Three synaptic conductance were modeled, each with different kinetics to represent a variety of different synaptic processes. In response to all three types of synaptic conductance, models containing gKL produced spike trains with irregular interspike intervals. Only models lacking gKL when driven by rapidly arriving small excitatory postsynaptic currents were capable of generating regular spiking.