Auditory cortex interneuron development requires cadherins operating hair-cell mechanoelectrical transduction

Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):7765-7774. doi: 10.1073/pnas.1703408114. Epub 2017 Jul 13.

Abstract

Many genetic forms of congenital deafness affect the sound reception antenna of cochlear sensory cells, the hair bundle. The resulting sensory deprivation jeopardizes auditory cortex (AC) maturation. Early prosthetic intervention should revive this process. Nevertheless, this view assumes that no intrinsic AC deficits coexist with the cochlear ones, a possibility as yet unexplored. We show here that many GABAergic interneurons, from their generation in the medial ganglionic eminence up to their settlement in the AC, express two cadherin-related (cdhr) proteins, cdhr23 and cdhr15, that form the hair bundle tip links gating the mechanoelectrical transduction channels. Mutant mice lacking either protein showed a major decrease in the number of parvalbumin interneurons specifically in the AC, and displayed audiogenic reflex seizures. Cdhr15- and Cdhr23-expressing interneuron precursors in Cdhr23-/- and Cdhr15-/- mouse embryos, respectively, failed to enter the embryonic cortex and were scattered throughout the subpallium, consistent with the cell polarity abnormalities we observed in vitro. In the absence of adhesion G protein-coupled receptor V1 (adgrv1), another hair bundle link protein, the entry of Cdhr23- and Cdhr15-expressing interneuron precursors into the embryonic cortex was also impaired. Our results demonstrate that a population of newborn interneurons is endowed with specific cdhr proteins necessary for these cells to reach the developing AC. We suggest that an "early adhesion code" targets populations of interneuron precursors to restricted neocortical regions belonging to the same functional area. These findings open up new perspectives for auditory rehabilitation and cortical therapies in patients.

Keywords: adhesion code; deafness; neuronal migration; parvalbumin interneurons; tip links.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Auditory Cortex / embryology*
  • Auditory Cortex / metabolism
  • Cadherin Related Proteins / genetics
  • Cadherin Related Proteins / metabolism*
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Polarity
  • Female
  • Interneurons / physiology*
  • Macaca
  • Male
  • Mechanotransduction, Cellular
  • Mice
  • Protein Precursors / genetics
  • Protein Precursors / metabolism*
  • Receptors, G-Protein-Coupled / metabolism

Substances

  • Cadherin Related Proteins
  • Cadherins
  • Cdh23 protein, mouse
  • Mass1 protein, mouse
  • Pcdh15 protein, mouse
  • Protein Precursors
  • Receptors, G-Protein-Coupled