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

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

Libé-Philippot B1,2,3, Michel V1,2,3, Boutet de Monvel J1,2,3, Le Gal S1,2,3, Dupont T1,2,3, Avan P4,5,6, Métin C7,8,9, Michalski N1,2,3, Petit C10,2,3,11,12.

Author information

1
Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, 75015 Paris, France.
2
UMRS 1120, INSERM, 75015 Paris, France.
3
Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Complexité du Vivant, 75005 Paris, France.
4
Laboratoire de Biophysique Sensorielle, Université Clermont Auvergne, 63000 Clermont-Ferrand, France.
5
UMR 1107, INSERM, 63000 Clermont-Ferrand, France.
6
Centre Jean Perrin, 63000 Clermont-Ferrand, France.
7
Institut du Fer à Moulin, 75005 Paris, France.
8
UMRS 839, INSERM, 75005 Paris, France.
9
Sorbonne Universités, Université Pierre et Marie Curie Paris 06, 75005 Paris, France.
10
Unité de Génétique et Physiologie de l'Audition, Institut Pasteur, 75015 Paris, France; christine.petit@pasteur.fr.
11
Syndrome de Usher et Autres Atteintes Rétino-Cochléaires, Institut de la Vision, 75012 Paris, France.
12
Collège de France, 75005 Paris, France.

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

PMID:
28705869
PMCID:
PMC5544301
DOI:
10.1073/pnas.1703408114
[Indexed for MEDLINE]
Free PMC Article

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