Invited reviewThe function of BDNF in the adult auditory system
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
References (175)
- et al.
Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture
Neuron
(1990) - et al.
Connecting the ear to the brain: molecular mechanisms of auditory circuit assembly
Prog. Neurobiol.
(2011) Local protein synthesis, actin dynamics, and LTP consolidation
Curr. Opin. Neurobiol.
(2008)- et al.
BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis
Prog. Neurobiol.
(2005) - et al.
The basolateral amygdala modulates specific sensory memory representations in the cerebral cortex
Neurobiol. Learn. Mem.
(2009) - et al.
Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro
Brain Res. Bull.
(2005) - et al.
Spontaneous retinal activity modulates BDNF trafficking in the developing chick visual system
Mol. Cell. Neurosci.
(2004) - et al.
The vestibular system
Curr. Biol.
(2005) - et al.
Role of endogenous opioid system in the regulation of the stress response
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2001) - et al.
The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function
Cell
(2003)
Complementary roles of BDNF and NT-3 in vestibular and auditory development
Neuron
Development of inner ear afferent connections: forming primary neurons and connecting them to the developing sensory epithelia
Brain Res. Bull.
The role of neurotrophic factors in regulating the development of inner ear innervation
Trends Neurosci.
Neurotrophins in the ear: their roles in sensory neuron survival and fiber guidance
Prog. Brain Res.
Dynamics of binaural processing in the mammalian sound localization pathway–the role of GABA(B) receptors
Hear. Res.
Effects of electrical stimulation of efferent olivocochlear neurons on cat auditory-nerve fibers. I. Rate-level functions
Hear. Res.
Distribution of BDNF, NT-3 and NT-4 in the developing auditory brainstem
Int. J. Dev. Neurosci.
First appearance of type II neurons during ontogenesis in the spiral ganglion of the rat. An immunocytochemical study
Brain Res. Dev. Brain Res.
BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex
Cell
Local presynaptic activity gates homeostatic changes in presynaptic function driven by dendritic BDNF synthesis
Neuron
Neurotransmission in the inner ear
Hear. Res.
Synaptophysin and GAP-43 proteins in efferent fibers of the inner ear during postnatal development
Brain Res. Dev. Brain Res.
Arc in synaptic plasticity: from gene to behavior
Trends Neurosci.
Spontaneous activity in the developing gerbil auditory cortex in vivo involves GABAergic transmission
Neuroscience
Effects of chronic cochlear de-efferentation on auditory-nerve response
Hear. Res.
Development of vestibular afferent projections into the hindbrain and their central targets
Brain Res. Bull.
The auditory system
Brain-derived neurotrophic factor-induced potentiation of glutamate and GABA release: different dependency on signaling pathways and neuronal activity
Mol. Cell. Neurosci.
Generators of the brainstem auditory evoked potential in cat. III: Identified cell populations
Hear. Res.
A rapid increase in the total number of cell surface functional GABAA receptors induced by brain-derived neurotrophic factor in rat visual cortex
J. Biol. Chem.
Opposite actions of brain-derived neurotrophic factor and neurotrophin-3 on firing features and ion channel composition of murine spiral ganglion neurons
J. Neurosci.
Mouse and rat BDNF gene structure and expression revisited
J. Neurosci. Res.
Anterograde transport of brain-derived neurotrophic factor and its role in the brain
Nature
Depression and Alzheimer's disease: is stress the initiating factor in a common neuropathological cascade?
J. Alzheimers Dis.
Spatial segregation of BDNF transcripts enables BDNF to differentially shape distinct dendritic compartments
Proc. Natl. Acad. Sci. U. S. A.
Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor
J. Neurosci.
Corticotropin-releasing hormone-mediated induction of intracellular signaling pathways and brain-derived neurotrophic factor expression is inhibited by the activation of the endocannabinoid system
Endocrinology
Arc-dependent synapse-specific homeostatic plasticity
Proc. Natl. Acad. Sci. U. S. A.
Development and evolution of the vestibular sensory apparatus of the mammalian ear
J. Vestib. Res.
Degeneration of vestibular neurons in late embryogenesis of both heterozygous and homozygous BDNF null mutant mice
Development
Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization?
Mol. Pain
LTP not equal learning: lessons from short-term plasticity
Front. Behav. Neurosci.
Onset coding is degraded in auditory nerve fibers from mutant mice lacking synaptic ribbons
J. Neurosci.
Encoding intensity in ventral cochlear nucleus following acoustic trauma: implications for loudness recruitment
J. Assoc. Res. Otolaryngol.
Distribution of brain-derived neurotrophic factor (BDNF) protein and mRNA in the normal adult rat CNS: evidence for anterograde axonal transport
J. Neurosci.
BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain
Nature
Properties of auditory nerve responses in absence of outer hair cells
J. Neurophysiol.
Cochlear efferent feedback balances interaural sensitivity
Nat. Neurosci.
Gradients of neurotrophins, ion channels, and tuning in the cochlea
Neuroscientist
Stress and the brain: from adaptation to disease
Nat. Rev. Neurosci.
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2020, Current Opinion in PhysiologyCitation Excerpt :Importantly, corticofugal projections have also been described from the frontal, somatosensory and visual cortices to the IC [9••]. The auditory efferent network is also interconnected with emotional and arousal circuits: the amygdala receives direct afferent projections from the auditory thalamus and efferent connections from the auditory cortex [4,10], while locus coeruleus neurons make synapses with olivocochlear neurons [11,12] and auditory cortex [13]. A summary of cognitive, emotional and arousal brain networks that could influence auditory efferents is presented in Figure 1.
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