Elsevier

Neuropharmacology

Volume 76, Part C, January 2014, Pages 719-728
Neuropharmacology

Invited review
The function of BDNF in the adult auditory system

https://doi.org/10.1016/j.neuropharm.2013.05.008Get rights and content

Highlights

  • BDNF expression in the auditory system.

  • The functional role of BDNF for the adult auditory system.

  • Role of BDNF in the peripheral and central auditory system following trauma.

Abstract

The inner ear of vertebrates is specialized to perceive sound, gravity and movements. Each of the specialized sensory organs within the cochlea (sound) and vestibular system (gravity, head movements) transmits information to specific areas of the brain. During development, brain-derived neurotrophic factor (BDNF) orchestrates the survival and outgrowth of afferent fibers connecting the vestibular organ and those regions in the cochlea that map information for low frequency sound to central auditory nuclei and higher-auditory centers. The role of BDNF in the mature inner ear is less understood. This is mainly due to the fact that constitutive BDNF mutant mice are postnatally lethal. Only in the last few years has the improved technology of performing conditional cell specific deletion of BDNF in vivo allowed the study of the function of BDNF in the mature developed organ. This review provides an overview of the current knowledge of the expression pattern and function of BDNF in the peripheral and central auditory system from just prior to the first auditory experience onwards. A special focus will be put on the differential mechanisms in which BDNF drives refinement of auditory circuitries during the onset of sensory experience and in the adult brain.

This article is part of the Special Issue entitled ‘BDNF Regulation of Synaptic Structure, Function, and Plasticity’.

Introduction

Brain derived neurotrophic factor (BDNF) was first described as a survival and growth factor in the developing central nervous system (CNS); for review: (Alderson et al., 1990; Hohn et al., 1990; Rodriguez-Tebar et al., 1990). Today the knowledge about the complex function of BDNF in the developed mammalian organ is continuously expanding. BDNF has several beneficial roles for normal body function, including maintenance of normal memory and cognitive functions (Bramham and Messaoudi, 2005; Egan et al., 2003; Lee and Hynds, 2013; Minichiello, 2009; Thoenen, 2000), maintenance of mature dendritic complexity and spine density in selected brain centers (Rauskolb et al., 2010), but also specific brain functions such as food intake (Gray et al., 2006). Much less understood are the potential harmful roles of BDNF as described for neuropathic pain (Biggs et al., 2010) or psychiatric and neurodegenerative disorders (Aznar and Knudsen, 2011; Hu and Russek, 2008; Krishnan and Nestler, 2010; Lu and Martinowich, 2008; Pardon, 2010). To what extent the different functions of BDNF are a result of the differential usage of distinct BDNF promoters is one of the most intriguing and challenging current research fields in neuroscience. The transcription of the BDNF gene in rodents is mediated by 9 alternative promoters linked to nine 5′ untranslated exons. Each 5′ exon is alternatively spliced to a downstream exon that contains the coding region of BDNF with a 3′ UTR containing two potential polyadenylation signals (Aid et al., 2007). All 22 different transcripts encode the same prepro-BDNF protein (Aid et al., 2007). Some promoters maintain basal levels of BDNF expression necessary for neuronal survival and differentiation, whereas others drive activity dependent BDNF expression (Baj et al., 2011; Koppel et al., 2009; Lu, 2003; Timmusk et al., 1993). Interestingly the human BDNF gene encodes two additional 5′ exons, Vh linked to an alternative promoter and VIIIh, which does not have an alternative promoter (Pruunsild et al., 2007). Additionally cryptic slpicing donor and acceptor sites are used in the human BDNF exon IX leading to transcripts which contain alternative splice variants of this exon (IXbd, IXabd) (Pruunsild et al., 2007). This makes the regulation of human BDNF even more complex.

In this review we will focus on the role of BDNF in the inner ear and central auditory pathway, with special focus on the critical period just prior to the onset of hearing and the mature organ. We will provide information relevant for understanding the function of BDNF during this period (Chapter 2) summarize information about the expression pattern of BDNF in the peripheral and central auditory system during this time (Chapter 3), outline findings about the function of BDNF in the peripheral and central auditory pathways from the first sensory experience onwards (Chapter 4) and we will examine the differential roles of BDNF in altering auditory circuitries during acoustically induced sensory trauma (Chapter 5, 6). To understand the role of BDNF in the neonatal organ we refer to several excellent reviews (Davis, 2003; Fritzsch et al., 2004; Ramekers et al., 2012; Schimmang and Represa, 1997).

Section snippets

Brief overview of the peripheral auditory pathway

In order to understand the role of BDNF in the developed auditory system, the most important compartments of this sensory organ have to be known. The inner ear of vertebrates is composed of three different sensory systems dedicated to the perception of sound, gravity and various head movements (Lewis et al., 1985) (Fig. 1 A). The connections between the ear and the brain develop such that each of the end organs transmits its information to specific areas of the brain (Maklad and Fritzsch, 2003;

BDNF expression in the peripheral auditory system

It is important to note that many aspects of BDNF biology in the adult sensory system have only recently come to light. In many organs and brain regions, the subcellular localization of this secreted protein within neurons is still unclear because of the very low levels of endogenous BDNF (Dieni et al., 2012). This is especially true for the mature inner ear, where the need to decalcify the bone in order to access the sensory organs often makes the analysis difficult. Appropriate ko mice as

Role of BDNF for fiber rearrangement

The functional role of BDNF in the neonatal development of the inner ear has been extensively reviewed (Bianchi et al., 1996; Davis, 2003; Ernfors et al., 1995; Farinas et al., 2001; Fritzsch, 2003; Fritzsch et al., 2000, 1997, 2004; Pirvola et al., 1992; Ramekers et al., 2012; Schimmang et al., 1995; Schimmang and Represa, 1997; Tessarollo et al., 2004, 1997).

Concurrent to the switch of BDNF expression from the sensory cells to the supporting cells and SGs prior to the onset of hearing (see

Role of BDNF in the peripheral and central auditory system following trauma

While profound acoustic trauma is linked to loss of OHCs, which are mostly responsible for hearing thresholds (Dallos and Harris, 1978; Moore and Vinay, 2009) recent studies showed that even moderate acoustic overexposure can lead to a rapid and irreversible loss of peripheral cochlear nerve terminals on IHCs (Kujawa and Liberman, 2009; Lin et al., 2011; Ruttiger et al., 2013). The reduction of synaptic ribbons is reported to lead to deafferentation that progresses over time and is followed by

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    Present address: DNA Genotek Inc., Ottawa, ON, Canada.

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