聴覚障害におけるグルタミン酸の役割

Abstract

L-Glutamate is believed to be a neurotransmitter in the first auditory synapse between the inner hair cells and the dendrites of spiral ganglion type I cells. It is released by a variety of mechanisms, such as anoxia, acoustic trauma and some ototoxic drugs. Although excessive release of glutamate is supposed to be toxic to the surrounding neurons, the exact mechanism of action in the cochlea remains unclear. In the first experiment, we investigated the effects of glutamate on hearing by the administration of AMPA, an agonist of glutamate, to the cochlea of guinea pigs. AMPA caused a reversible increase in the threshold of the compound action potential (CAP). Secondly, we studied the glutamate excitotoxicity induced by transient cochlear anoxia by means of occlusion of the bilateral vertebral arteries in gerbils. Five minutes of occlusion caused a drastic increase in the CAP threshold, which recovered after recirculation. The threshold returned to preischemic levels on the 3rd day, but in some animals it increased again after the 5th day, suggesting delayed neuronal death. Glutamate concentration in the perilymph increased following ischemic insult. Histological studies revealed that ischemic pathological changes were severe in the dendrites of the primary afferent auditory nerve, composing the synapse with the inner hair cell. In the 3rd experiment, the effects of noise exposure on hearing were studied in mice lacking the glutamate transporter GLAST (mutant mice). Continuous 4kHz pure tone exposure of 105dB for 30 minutes caused an increase in the CAP threshold in both mutant and wild mice. However, the increase was more severe and the recovery was later in mutant than in wild mice. Glutamate concentration in the perilymph was consistently higher in the former than in the latter. These results suggested that excessive glutamate released in the cochlea as a consequence of anoxia or acoustic trauma caused damage to the surrounding neurons, especially to the dendrites of the primary afferent auditory nerve. Glutamate excitotoxicity is, therefore, thought to underlie sensory hearing loss attributed to a variety of causes.