Excitotoxicity, synaptic repair, and functional recovery in the mammalian cochlea: a review of recent findings.
Besides its fast excitatory properties, glutamate is known to have neurotoxic properties when released in large amounts or when incompletely recycled. This so-called excitotoxicity is involved in a number of acute and/or degenerative forms of neuropathology such as epilepsy, Alzheimer's, Parkinson's, stroke, and retinal ischemia. In the cochlea, excitotoxicity may occur in two pathological conditions: anoxia and noise trauma. It is characterized by a two-step mechanism: (1) An acute swelling, which primarily depends on the AMPA/kainate type of receptors, together with a disruption of the postsynaptic structures (type I afferent dendrites) resulting in a loss of function. Within the next 5 days, synaptic repair may be observed with a full or a partial (acoustic trauma) recovery of cochlear potentials. (2) The second phase of excitotoxicity, which may develop after strong and/or repetitive injury, consists of a cascade of metabolic events triggered by the entry of Ca2+, which leads to neuronal death in the spiral ganglion. Ongoing experiments in animals, tracking the molecular basis of both these processes, presages the development of new pharmacological strategies to help neurites to regrow and reconnect properly to the IHCs, and to prevent or delay neuronal death in the spiral ganglion. Human applications should follow, and a local (transtympanic) strategy against cochlear excitotoxicity may, in the near future, prove to be helpful in ischemic- or noise-induced sudden deafness, as well as in the related tinnitus.
Pujol
R
R
INSERM, Montpellier, France. rpujol@montp.inserm.fr
Puel
J L
JL
D000818:Animals; D003051:Cochlea / Q000187:drug effects* / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000009:adverse effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006168:Guinea Pigs; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects / Q000502:physiology; D006317:Hearing Loss, Noise-Induced / Q000188:drug therapy*; D009498:Neurotoxins / Q000009:adverse effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013569:Synapses / Q000187:drug effects* / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate