Functional role of GABAergic innervation of the cochlea: phenotypic analysis of mice lacking GABA(A) receptor subunits alpha 1, alpha 2, alpha 5, alpha 6, beta 2, beta 3, or delta.
The olivocochlear efferent system is both cholinergic and GABAergic and innervates sensory cells and sensory neurons of the inner ear. Cholinergic effects on cochlear sensory cells are well characterized, both in vivo and in vitro; however, the robust GABAergic innervation is poorly understood. To explore the functional roles of GABA in the inner ear, we characterized the cochlear phenotype of seven mouse lines with targeted deletion of a GABA(A) receptor subunit (alpha1, alpha2, alpha5, alpha6, beta2, beta3, or delta). Four of the lines (alpha1, alpha2, alpha6, and delta) were normal: there was no cochlear histopathology, and cochlear responses suggested normal function of hair cells, afferent fibers, and efferent feedback. The other three lines (alpha5, beta2, and beta3) showed threshold elevations indicative of outer hair cell dysfunction. Alpha5 and beta2 lines also showed decreased effects of efferent bundle activation, associated with decreased density of efferent terminals on outer hair cells: although the onset of this degeneration was later in alpha5 (>6 weeks) than beta2 (<6 weeks), both lines shows normal efferent development (up to 3 weeks). Two lines (beta2 and beta3) showed signs of neuropathy, either decreased density of afferent innervation (beta3) or decreased neural responses without concomitant attenuation of hair cell responses (beta2). One of the lines (beta2) showed a clear sexual dimorphism in cochlear phenotype. Results suggest that the GABAergic component of the olivocochlear system contributes to the long-term maintenance of hair cells and neurons in the inner ear.
Maison
Stéphane F
SF
Department of Otology and Laryngology, Harvard Medical School and Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA. stephane_maison@meei.harvard.edu
Rosahl
Thomas W
TW
Homanics
Gregg E
GE
Liberman
M Charles
MC
D000161:Acoustic Stimulation / Q000379:methods; D000818:Animals; D003051:Cochlea / Q000294:innervation* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D021122:Protein Subunits; D064529:Receptor, Metabotropic Glutamate 5; D018079:Receptors, GABA; D011963:Receptors, GABA-A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate; D013045:Species Specificity; D005680:gamma-Aminobutyric Acid
C546241:Gabra1 protein, mouse; C493920:Gabra2 protein, mouse; C546172:Gabra6 protein, mouse; C470436:Gabrb2 protein, mouse; C546270:Gabrb3 protein, mouse; D021122:Protein Subunits; D064529:Receptor, Metabotropic Glutamate 5; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D005680:gamma-Aminobutyric Acid