Lack of Brain-Derived Neurotrophic Factor Hampers Inner Hair Cell Synapse Physiology, But Protects against Noise-Induced Hearing Loss

Abstract

The precision of sound information transmitted to the brain depends on the transfer characteristics of the inner hair cell (IHC) ribbon synapse and its multiple contacting auditory fibers. We found that brain derived neurotrophic factor (BDNF) differentially influences IHC characteristics in the intact and injured cochlea. Using conditional knock-out mice (BDNF Pax2 KO) we found that resting membrane potentials, membrane capacitance and resting linear leak conductance of adult BDNF Pax2 KO IHCs showed a normal maturation. Likewise, in BDNF Pax2 KO membrane capacitance (⌬C m ) as a function of inward calcium current (I Ca ) follows the linear relationship typical for normal adult IHCs. In contrast the maximal ⌬C m , but not the maximal size of the calcium current, was significantly reduced by 45% in basal but not in apical cochlear turns in BDNF Pax2 KO IHCs. Maximal ⌬C m correlated with a loss of IHC ribbons in these cochlear turns and a reduced activity of the auditory nerve (auditory brainstem response wave I). Remarkably, a noise-induced loss of IHC ribbons, followed by reduced activity of the auditory nerve and reduced centrally generated wave II and III observed in control mice, was prevented in equally noise-exposed BDNF Pax2 KO mice. Data suggest that BDNF expressed in the cochlea is essential for maintenance of adult IHC transmitter release sites and that BDNF upholds opposing afferents in high-frequency turns and scales them down following noise exposure.

Innervation regulates synaptic ribbons in lateral line mechanosensory hair cells

“…Similarly, ribbons are found in positions other than the synapse in cochlear hair cells of guinea pigs after the post-synaptic fibers are damaged following intracochlear perfusion with 200 μM AMPA (Puel et al, 1995). Furthermore, the number of hair cell ribbons, as assessed by immunohistochemistry, is decreased in brain-derived neurotrophic factor (BDNF)-or Mafb-knockout postnatal mice, where innervation is reduced or delayed (Zuccotti et al, 2012;Yu et al, 2013), and in adult mice when ouabain is applied in the round window causing de-afferentation of cochlear hair cells (Yuan and Chi, 2014). Although these observations were made either with in vitro preparations, such as the cultured cochlea, or in conditions which might affect both the nerve and the hair cells, such as in BDNF mutants and in treated cochlea, these studies suggest that innervation is required for localizing ribbons at the synapse and regulating their number in mechanosensory hair cells.…”

Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death

“…4 SCs perform many functions, including providing critical trophic factors, preventing excitotoxicity, and mediating regeneration in those systems (non-mammalian vertebrates) capable of replacing lost HCs. [5][6][7][8][9][10][11] When HCs die, SCs also preserve the integrity and function of the remaining tissue by forming scars and clearing dead HCs. 2,[12][13][14][15][16][17] Maintaining a fluid barrier at the surface of the sensory epithelium after damage is necessary to preserve the electro-chemical gradient that drives HC depolarization and therefore sensory transduction after the onset of hearing (reviewed in Wangemann).…”

Biomarkers for Hearing Dysfunction: Facts and Outlook

“…In conclusion, an increasing number of studies have now demonstrated that the counting of IHC ribbons after hearing loss, for example, in aged specimens [62,64] , or after an acoustic trauma [22,31,32,61,75,76] , or after intake of aminoglycoside [77,78] , can be a first indication of the loss of IHC synapses and AN integrity, independent of (elevated) hearing thresholds.…”