Synaptic repair mechanisms responsible for functional recovery in various cochlear pathologies.
In some cochlear pathologies, temporary hearing loss can be followed by complete or partial functional recovery. Our previous findings suggest the involvement of an excitotoxic (glutamate-related) disruption of inner hair cell (IHC)-auditory nerve synapses, followed by synaptic regeneration. It is essential to understand the molecular mechanisms responsible for this synaptic repair if new therapeutic strategies are to be developed. In guinea pig cochleas, acute synaptic excitotoxic damage (mimicking what occurs with acoustic trauma or local ischemia) is achieved by locally applying AMPA, a glutamate agonist. This results in a total disruption of all IHC-auditory dendrite synapses, together with a disappearance of cochlear potentials. Within the next 5 days, however, a recovery of both the normal pattern of IHC innervation and the physiological responses is observed. The fact that the blockage of the NMDA receptors during functional recovery delayed the regrowth of neurites and the restoration of hearing suggests that glutamate plays a neurotrophic role via activation of NMDA receptors. Experiments are in progress to investigate, among other factors, the role of other glutamate receptor subunits. A reversible in vivo antisense strategy is being developed to overcome the lack of specificity of some antagonists. First results bode well for future pharmacological therapies in cochlear pathologies where glutamatergic synapses are likely to be involved; i.e., noise trauma, ischemia-related sudden deafness, and neural presbycusis.
Puel
J L
JL
INSERM U.254 et Université de Montpellier I, Laboratoire de Neurobiologie de l'Audition-Plasticité synaptique, France. puel@infobiogen.fr
d'Aldin
C
C
Ruel
J
J
Ladrech
S
S
Pujol
R
R
D000818:Animals; D003051:Cochlea / Q000503:physiopathology; D015834:Cochlear Diseases / Q000503:physiopathology*; D003712:Dendrites / Q000187:drug effects / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006168:Guinea Pigs; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects / Q000503:physiopathology*; D006309:Hearing; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009416:Nerve Regeneration; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D013569:Synapses / Q000502:physiology; D000159:Vestibulocochlear Nerve / Q000187:drug effects / Q000503:physiopathology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid