Orphan glutamate receptor δ1 subunit required for high-frequency hearing

The function of the orphan glutamate receptor delta subunits (GluR delta 1 and GluR delta 2) remains unclear. GluR delta 2 is expressed exclusively in the Purkinje cells of the cerebellum, and GluR delta 1 is prominently expressed in inner ear hair cells and neurons of the hippocampus. We found that mice lacking the GluR delta 1 protein displayed significant cochlear threshold shifts for frequencies of >16 kHz. These deficits correlated with a substantial loss of type IV spiral ligament fibrocytes and a significant reduction of endolymphatic potential in high-frequency cochlear regions. Vulnerability to acoustic injury was significantly enhanced; however, the efferent innervation of hair cells and the classic efferent inhibition of outer hair cells were unaffected. Hippocampal and vestibular morphology and function were normal. Our findings show that the orphan GluR delta 1 plays an essential role in high-frequency hearing and ionic homeostasis in the basal cochlea, and the locus encoding GluR delta 1 represents a candidate gene for congenital or acquired high-frequency hearing loss in humans.