Puel J L, d'Aldin C, Ruel J, Ladrech S, Pujol R
INSERM U.254 et Université de Montpellier I, Laboratoire de Neurobiologie de l'Audition-Plasticité synaptique, France.
Acta Otolaryngol. 1997 Mar;117(2):214-8. doi: 10.3109/00016489709117773.
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.
在某些耳蜗病变中，暂时性听力损失之后可能会出现完全或部分功能恢复。我们之前的研究结果表明，内毛细胞（IHC）-听觉神经突触存在兴奋性毒性（与谷氨酸相关）破坏，随后会发生突触再生。如果要开发新的治疗策略，了解负责这种突触修复的分子机制至关重要。在豚鼠耳蜗中，通过局部应用谷氨酸激动剂AMPA可实现急性突触兴奋性毒性损伤（模拟声学创伤或局部缺血时发生的情况）。这会导致所有IHC-听觉树突突触完全破坏，同时耳蜗电位消失。然而，在接下来的5天内，可观察到IHC神经支配的正常模式和生理反应均恢复。功能恢复期间NMDA受体被阻断会延迟神经突的再生和听力恢复，这一事实表明谷氨酸通过激活NMDA受体发挥神经营养作用。正在进行实验以研究其他因素，包括其他谷氨酸受体亚基的作用。正在开发一种可逆的体内反义策略，以克服某些拮抗剂缺乏特异性的问题。初步结果为未来在可能涉及谷氨酸能突触的耳蜗病变（即噪声性创伤、缺血性突发性耳聋和神经性老年性聋）中的药物治疗带来了良好的预兆。
