Brain-Derived Neurotrophic Factor Modulates Auditory Function in the Hearing Cochlea

Abstract

Neurotrophins prevent spiral ganglion neuron (SGN) degeneration in animal models of ototoxin-induced deafness and may be used in the future to improve the hearing of cochlear implant patients. It is increasingly common for patients with residual hearing to undergo cochlear implantation. However, the effect of neurotrophin treatment on acoustic hearing is not known. In this study, brain-derived neurotrophic factor (BDNF) was applied to the round window membrane of adult guinea pigs for 4 weeks using a cannula attached to a mini-osmotic pump. SGN survival was first assessed in ototoxically deafened guinea pigs to establish that the delivery method was effective. Increased survival of SGNs was observed in the basal and middle cochlear turns of deafened guinea pigs treated with BDNF, confirming that delivery to the cochlea was successful. The effects of BDNF treatment in animals with normal hearing were then assessed using distortion product otoacoustic emissions (DPOAEs), pure tone, and clickevoked auditory brainstem responses (ABRs). DPOAE assessment indicated a mild deficit of 5 dB SPL in treated and control groups at 1 and 4 weeks after cannula placement. In contrast, ABR evaluation showed that BDNF lowered thresholds at specific frequencies (8 and 16 kHz) after 1 and 4 weeks posttreatment when compared to the control cohort receiving Ringer's solution. Longer treatment for 4 weeks not only widened the range of frequencies ameliorated from 2 to 32 kHz but also lowered the threshold by at least 28 dB SPL at frequencies ≥16 kHz. BDNF treatment for 4 weeks also increased the amplitude of the ABR response when compared to either the control cohort or prior to treatment. We show that BDNF applied to the round window reduces auditory thresholds and could potentially be used clinically to protect residual hearing following cochlear implantation.

Combined application of brain-derived neurotrophic factor and neurotrophin-3 and its impact on spiral ganglion neuron firing properties and hyperpolarization-activated currents

“…Further, this outcome is consistent with recent in vivo outcomes (Landry et al, 2011). Following combined BDNF and NT3 delivery in the deafened guinea pig model, thresholds of electrically evoked auditory brainstem responses in neurotrophin-treated animals were lowered relative to treatment with artificial perilymph (Landry et al, 2011;Sly et al, 2012). This effect was also reported with BDNF alone (Agterberg et al, 2009;Leake et al, 2011;Shepherd et al, 2005;Shinohara et al, 2002).…”

“…This effect was also reported with BDNF alone (Agterberg et al, 2009;Leake et al, 2011;Shepherd et al, 2005;Shinohara et al, 2002). Moreover, these neurotrophinmediated outcomes were not limited to the deafened system or electrical stimulation, since BDNF application in animals with normal hearing also resulted in a reduction of thresholds in the acoustically-evoked auditory brainstem response (Sly et al, 2012). Our results lend support to these previous findings by confirming that thresholds are reduced at the single neuron level in the presence of combined application of BDNF and NT3.…”

“…Such deafnessinduced changes in the SGN population include alterations to spike latency, jitter, threshold, adaptation (nerve responsiveness), and responses to high-frequency stimulation (Heffer et al, 2010;Sly et al, 2007). Remarkably, exogenous BDNF applied in vivo can help preserve the normal function of the nerve , and even enhance the sensitivity to sound stimuli in animals with residual hearing (Sly et al, 2012). Electrophysiological studies in early post-natal murine SGNs have also shown differences in firing patterns following exposure to either BDNF or NT3 for a week in vitro (Adamson et al, 2002a;Zhou et al, 2005).…”

“…Modelling studies of auditory nerve fibres also identify a role for I h in firing threshold and adaptation (Negm and Bruce, 2008). Since these are firing properties altered with deafness and neurotrophin application (Adamson et al, 2002a;Sly et al, 2007Sly et al, , 2012Zhou et al, 2005), we sought to investigate the influence of combined BDNF and NT3 application on I h in SGNs. Here we use whole-cell recordings in dissociated early post-natal rat SGNs cultured in the presence or absence of BDNF and NT3 for 1 or 2 days and report on the impact of combined neurotrophins on SGN firing properties and I h activity.…”

Firing frequency and entrainment maintained in primary auditory neurons in the presence of combined BDNF and NT3

“…To determine the functional outcomes of neurotrophin delivery, both in vivo and in vitro studies have examined the impact of BDNF and/or NT3 on neuronal activity6232425. Initial in vitro studies revealed that BDNF and NT3 had opposing effects on SGNs, and suggested that application of one or the other would propagate different firing patterns2.…”