Complex Regulation of Spiral Ganglion Neuron Firing Patterns by Neurotrophin-3

Abstract

Auditory information is conveyed into the CNS via the spiral ganglion neurons, cells that possess distinctive electrophysiological properties that vary according to their cochlear innervation. Neurons from the base of the cochlea fire action potentials with shorter latencies and durations with more rapid accommodation than apical neurons (Adamson et al., 2002b). Interestingly, these features are altered by exposure to brain-derived neurotrophic factor and neurotrophin-3 (NT-3), suggesting that the electrophysiological diversity is not preprogrammed into the neurons but instead results from extrinsic regulation. In support of this, gradients of neurotrophins exist in the cochlea that could account for the apex-base differences in firing. To understand the determinants of spiral ganglion function, we characterized the NT-3 concentration dependence and mode of action on spiral ganglion neurons. Whole-cell current-clamp recordings were made from mouse basal spiral ganglion neurons (postnatal day 5) exposed to different concentrations of NT-3 for 3 d in vitro. Measurements of accommodation, latency, onset time course, and action potential latency revealed a nonmonotonic dependence on NT-3 concentration, with a peak effect occurring at 10 ng/ml. Addition of NT-3 at different time points showed that neurotrophin exposure altered the firing features of existing neurons rather than supporting differential survival. These experiments establish that the electrophysiological phenotype of spiral ganglion neurons depends critically on the precise concentration of NT-3 and that the functional organization of this component of the peripheral auditory system results from a complex interplay between multiple kinds of neurotrophins and their cognate receptors.

Reciprocal Regulation of Presynaptic and Postsynaptic Proteins in Bipolar Spiral Ganglion Neurons by Neurotrophins

“…Another aspect of this reciprocal regulation is the apparent homogeneity in the neuronal population exposed to BDNF compared with the heterogeneity observed with NT-3. These differences have also been observed with previous electrophysiological analysis (Adamson et al, 2002b;Zhou et al, 2005); the functional significance, however, has yet to be explored directly.…”

“…Presynaptic and postsynaptic proteins are differentially distributed within the spiral ganglion Previous studies have shown that although 95% of the neurons within the spiral ganglion are of one class, they display clear differences in their ion channel composition and resulting firing patterns (Mo and Davis, 1997;Adamson et al, 2002b;Reid et al, 2004;Zhou et al, 2005). Neurons that innervate high frequency sensory receptors at the basal end of the cochlea possess voltagegated ion channel types that mediate abbreviated and rapidly accommodating responses to prolonged step depolarizations.…”

“…The first was a neuronal culture in which the apical and basal one-fifth of the spiral ganglion were isolated from postnatal day 7 (P7) CBA/CaJ mice and plated in separate culture dishes; then used after 6 d in vitro (div). This preparation was used to compare new data directly with previous investigations in which electrophysiological parameters have been fully characterized along with extensive immunocytochemical, pharmacological, and molecular studies of the underlying voltage-gated ion channel contributions (Adamson et al, 2002a,b;Reid et al, 2004;Zhou et al, 2005;Chen and Davis, 2006). In all cultures, cells were maintained in growth medium: DMEM (Sigma D6171) supplemented with 10% fetal bovine serum, 4 mM L-glutamine, and 0.1% penicillin-streptomycin.…”

Unmasking of Spiral Ganglion Neuron Firing Dynamics by Membrane Potential and Neurotrophin-3

“…To determine potential mediators of these changes, we examined the effects of NT-3, the expression of which is reduced during this same time period. Based upon previous studies, we expected that P5 basal spiral ganglion neurons would be converted from RA to SA, that voltage thresholds would be reduced, and that latencies would be prolonged after exogenous application of NT-3 (Adamson et al, 2002b;Zhou et al, 2005). Here, we expanded on those observations by assessing the effects of NT-3 (10 ng/ml) on basal and apical neurons by examining both earlier (P3, slower but highly excitable), intermediate (P8), and later (P10-P14, faster but reduced excitability) time points.…”

“…The stock solution was diluted with sterile distilled water and added at time of plating to a final concentration of 10 ng/ml (1:1000 dilution). This concentration was chosen because it yielded the maximal change in accommodation (Zhou et al, 2005). Vehicle control was 10 l of sterile distilled water added at time of plating.…”