Activity-dependent, homeostatic regulation of neurotransmitter release from auditory nerve fibers

Proc Natl Acad Sci U S A. 2015 May 19;112(20):6479-84. doi: 10.1073/pnas.1420885112. Epub 2015 May 5.


Information processing in the brain requires reliable synaptic transmission. High reliability at specialized auditory nerve synapses in the cochlear nucleus results from many release sites (N), high probability of neurotransmitter release (Pr), and large quantal size (Q). However, high Pr also causes auditory nerve synapses to depress strongly when activated at normal rates for a prolonged period, which reduces fidelity. We studied how synapses are influenced by prolonged activity by exposing mice to constant, nondamaging noise and found that auditory nerve synapses changed to facilitating, reflecting low Pr. For mice returned to quiet, synapses recovered to normal depression, suggesting that these changes are a homeostatic response to activity. Two additional properties, Q and average excitatory postsynaptic current (EPSC) amplitude, were unaffected by noise rearing, suggesting that the number of release sites (N) must increase to compensate for decreased Pr. These changes in N and Pr were confirmed physiologically using the integration method. Furthermore, consistent with increased N, endbulbs in noise-reared animals had larger VGlut1-positive puncta, larger profiles in electron micrographs, and more release sites per profile. In current-clamp recordings, noise-reared BCs had greater spike fidelity even during high rates of synaptic activity. Thus, auditory nerve synapses regulate excitability through an activity-dependent, homeostatic mechanism, which could have major effects on all downstream processing. Our results also suggest that noise-exposed bushy cells would remain hyperexcitable for a period after returning to normal quiet conditions, which could have perceptual consequences.

Keywords: cochlear nucleus; homeostasis; release probability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acoustic Stimulation
  • Animals
  • Auditory Perception / physiology*
  • Brain Stem / physiology*
  • Cochlear Nerve / metabolism
  • Cochlear Nerve / physiology*
  • Excitatory Postsynaptic Potentials / physiology
  • Homeostasis / physiology*
  • Immunohistochemistry
  • Mice
  • Microscopy, Electron
  • Neurotransmitter Agents / metabolism*
  • Noise / adverse effects
  • Patch-Clamp Techniques
  • Synapses / metabolism
  • Synapses / physiology*
  • Synapses / ultrastructure


  • Neurotransmitter Agents