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. 2012 May 22;109(21):8292-7.
doi: 10.1073/pnas.1116981109. Epub 2012 May 7.

Mechanisms contributing to central excitability changes during hearing loss

Nadia Pilati  1 , Matias J Ison, Matthew Barker, Mike Mulheran, Charles H Large, Ian D Forsythe, John Matthias, Martine Hamann
Affiliations

Mechanisms contributing to central excitability changes during hearing loss

Nadia Pilati et al. Proc Natl Acad Sci U S A. .

Abstract

Exposure to loud sound causes cochlear damage resulting in hearing loss and tinnitus. Tinnitus has been related to hyperactivity in the central auditory pathway occurring weeks after loud sound exposure. However, central excitability changes concomitant to hearing loss and preceding those periods of hyperactivity, remain poorly explored. Here we investigate mechanisms contributing to excitability changes in the dorsal cochlear nucleus (DCN) shortly after exposure to loud sound that produces hearing loss. We show that acoustic overexposure alters synaptic transmission originating from the auditory and the multisensory pathway within the DCN in different ways. A reduction in the number of myelinated auditory nerve fibers leads to a reduced maximal firing rate of DCN principal cells, which cannot be restored by increasing auditory nerve fiber recruitment. In contrast, a decreased membrane resistance of DCN granule cells (multisensory inputs) leads to a reduced maximal firing rate of DCN principal cells that is overcome when additional multisensory fibers are recruited. Furthermore, gain modulation by inhibitory synaptic transmission is disabled in both auditory and multisensory pathways. These cellular mechanisms that contribute to decreased cellular excitability in the central auditory pathway are likely to represent early neurobiological markers of hearing loss and may suggest interventions to delay or stop the development of hyperactivity that has been associated with tinnitus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
AOE down-regulates AN and MS synaptic transmission to FCs. (A) AN inputs directly terminate onto FC basal dendrites in the deep layer (DL). (B) AN stimulations (25 V, 0.3 Hz) trigger smaller EPSPs after AOE (blue). Membrane potential was −70 mV. Histogram summarizes EPSP amplitudes measured at similar stimulating voltages in unexposed (25 ± 4 V, n = 4) and exposed conditions (28 ± 2 V, n = 6). (C) In unexposed condition (black), AN stimulations (40 V, 0.3 Hz) trigger action potentials in a FC (membrane potential of −60 mV). After AOE (blue), AN stimulations (40–45 V, 0.3 Hz) fail to trigger action potentials. (D) MS inputs originate from parallel fibers (PF), which are the granule cell (gc) axons terminating onto FC apical dendrites in the molecular layer (ML). (E) MS stimulations (15 V, 0.3 Hz) trigger smaller EPSPs after AOE (blue). Membrane potential was −70 mV. Histogram summarizes EPSP amplitudes measured at similar stimulating voltages in unexposed (16 ± 1 V, n = 8) and exposed conditions (19 ± 2 V, n = 6). (F) In unexposed condition (black), MS stimulations (20 V, 0.3 Hz) trigger action potentials in a FC (membrane potential of −60 mV). After AOE (blue), higher stimulation voltages (25 V, 0.3 Hz) are required to trigger an action potential. *P < 0.05, **P < 0.01: unpaired t tests.
Fig. 2.
Fig. 2.
AOE modulates FC transfer function upon AN and MS stimulation. (A) AN inputs were stimulated from 10 to 100 Hz. Average input–output relationships (n = 5–6) were obtained in unexposed condition (black) and after AOE (blue). Experimental and model data are represented, and lines are fits to a Hill function as detailed in SI Methods. (B) Transmitted electron micrographs of peripheral AN fibers in control condition (black frame) and after AOE (blue frame) at the base and the apex of the cochlea. Histograms represent the percentage of myelinated AN fibers in those conditions. (Scale bar: 1 μm.) (C and D) MS inputs (n = 5–6) were stimulated, and experimental and model data were fitted as described in A. Firing frequencies were measured at suprathreshold (C) and threshold (D) stimulating voltages. (E) Traces represent the granule cell firing in response to 1-s, 30-pA step current injections in unexposed condition (black) and after AOE (blue). Transfer functions for the two cells are shown. Histograms show that AOE decreases the granule cell membrane resistance and firing gain, leaving the maximal firing frequency unaffected (n = 9–10 per condition). Granule cell resting potentials were more hyperpolarized after AOE. *P < 0.05, **P < 0.01, ***P < 0.001: unpaired t tests.
Fig. 3.
Fig. 3.
FC gain control via inhibitory synaptic transmission is disabled after AOE. (A) AN inputs directly terminate in tuberculo ventral cells (Tv), which inhibit FCs. (B) AN stimulations (25 V, 0.3 Hz) trigger smaller IPSPs after AOE (blue). Membrane potential was −70 mV. (C) MS inputs directly terminate onto cartwheel cells (Cw), which inhibit FCs. (D) MS stimulations (25 V, 0.3 Hz) trigger smaller IPSPs after AOE (blue). Membrane potential was −70 mV. (E–H) Average input–output relationships (n = 5–6) were obtained following AN (E and G) and MS (F and H) stimulations before (solid line) and after (dashed line) removal of synaptic inhibition. (G) Note that inhibitory synaptic transmission has a reduced modulatory effect at threshold which disappears at supra-threshold stimulating voltages. Experimental data are represented in control (E and F) and after AOE (G and H), and lines are fits to a Hill function as detailed in SI Methods. Histograms represent the changes in the gain before and after removal of synaptic inhibition. **P < 0.01: unpaired t tests.
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