Heterogeneous intrinsic excitability of murine spiral ganglion neurons is determined by Kv1 and HCN channels

Abstract

The spiral ganglion conveys afferent auditory information predominantly through a single class of type I neurons that receive signals from inner hair cell (IHC) sensory receptors. These auditory primary afferents, like in other systems (Puopolo and Belluzzi, 1998, Gascon and Moqrich, 2010, Leao et al., 2012) possess a marked diversity in their electrophysiological features (Taberner and Liberman, 2005). Consistent with these observations, when the auditory primary afferents were assessed in neuronal explants separated from their peripheral and central targets it was found that individual neurons were markedly heterogeneous in their endogenous electrophysiological features. One aspect of this heterogeneity, obvious throughout the ganglion, was their wide range of excitability as assessed by voltage threshold measurements (Liu and Davis, 2007). Thus, while neurons in the base differed significantly from apical and middle neurons in their voltage thresholds, each region showed distinctly wide ranges of values. To determine whether the resting membrane potentials (RMP) of these neurons correlate with the threshold distribution and to identify the ion channel regulatory elements underlying heterogeneous neuronal excitability in the ganglion, patch-clamp recordings were made from postnatal day (P5-8) murine spiral ganglion neurons in vitro. We found that RMP mirrored the tonotopic threshold distribution, and contributed an additional level of heterogeneity in each cochlear location. Pharmacological experiments further indicated that threshold and RMP was coupled through the Kv1 current, which had a dual impact on both electrophysiological parameters. Whereas, hyperpolarization-activated cationic channels (HCN) decoupled these two processes by primarily affecting RMP without altering threshold level. Thus, beyond mechanical and synaptic specializations, ion channel regulation of intrinsic membrane properties imbues spiral ganglion neurons with different excitability levels, a feature that contributes to primary auditory afferent diversity.

I h and HCN Channels in Murine Spiral Ganglion Neurons: Tonotopic Variation, Local Heterogeneity, and Kinetic Model

“…Compared to V h ranging from −65 to −90 mV in these neurons, V h in SGNs is at least 10 mV more negative, and as a result, only 3 % of I h should be present at rest. When blocked by Cs + , this amount of I h is shown to hyperpolarize the RMP by 4 mV (Liu et al 2013). These results are consistent with those recordings made ex vivo from the nerve terminals (Yi et al 2010).…”

“…While a portion of the mechanism contributing to the threshold variation is based on synaptic mechanisms (Liberman et al 2011;Wong et al 2013), it is also possible that adjustment of the neuronal excitability post-synaptically could play a role. We recently found that spiral ganglion neuron firing thresholds are largely controlled by K v 1 potassium channels, while a negative V h of I h seems to prevent neurons with the lowest voltage threshold from spontaneous firing (Liu et al 2013). Consistent with this mechanism, modulation of I h by cAMP produces a positive shift in V h that enhances neural excitability and spontaneous discharge in superior olivary complex neurons (Shaikh and Finlayson 2005) in vivo.…”

“…First found in the sinoatrial node (Noma and Irisawa 1976) and soon confirmed to exist in many systems (Robinson and Siegelbaum 2003), the I h current impacts both synaptic integration and regulation of neuronal excitability. In the predominant type I neurons of the spiral ganglion, the I h current reduces the temporal summation of excitatory postsynaptic potentials in dendrites and regulates the resting membrane potential in both dendrites (Yi et al 2010) and the somata (Liu et al 2013).…”

Temporal Considerations for Stimulating Spiral Ganglion Neurons with Cochlear Implants

“…The kinetics of both channel types operate at slower timescales than the Hodgkin-Huxley channels (Rothman and Manis 2003;Liu et al 2014b). KLT channels are responsible for increasing the cell's voltage threshold and hyperpolarizing the resting membrane potential (Liu et al 2014a). HCN channels are well known for being permeable to Na + and K + with ratios ranging from 1:3 to 1:5 (Biel et al 2009).…”

“…When HCN is activated under membrane hyperpolarization, this generates a dominant inward Na + current which helps return the membrane potential back towards rest. HCN channels contribute to stabilizing the resting membrane potential of SGNs (Liu et al 2014a;Liu et al 2014b), a function that HCN appears to fulfill in a range of different cell types (Robinson and Siegelbaum 2003;Howells et al 2012;Benarroch 2013). An interesting property of the current produced by HCN channels, known as I h , is that it can increase the neuron's firing by a rebound excitation which happens towards the end of a hyperpolarizing pulse (Chen 1997).…”