From development to disease: Diverse functions of NMDA-type glutamate receptors in the lower auditory pathway

Abstract

N-methyl-D-aspartate receptors (NMDA-Rs) are located at each synapse in the lower auditory pathway of mammals and avians. Characterized by a slow and long-lasting excitatory response upon glutamate activation, their existence in a sensory system biologically engineered for speed and precision seems counterintuitive. In this review we consider the diverse functions of NMDA-Rs. Their developmental regulation and unique subunit composition in the inner ear promote protective and neurotrophic roles following acute insult by regulating AMPA-R expression and assisting in the restoration of synaptic inputs. This contrasts with chronic damage where overactivation of NMDA-Rs is implicated in neuronal death. These functions are thought to be involved in auditory diseases, including noise-induced hearing loss, neural presbycusis, and tinnitus via aberrant excitation. A more traditional role emerges in the developing auditory brainstem, where NMDA-Rs are downregulated and switch subunit composition with maturation. Their biophysical properties also contribute to synaptic dynamics resembling long-term plasticity. At mature synapses they support reliable auditory processing by increasing the probability of action potential generation, regulating first-spike latency, and maintaining reliable action potential firing. Thus, NMDA-R functions in the lower auditory pathway are diverse, contributing to synaptic development, plasticity, temporal processing, and diseases.

Auditory dysfunction in schizophrenia: integrating clinical and basic features

“…Notably, however, performance on tests of this type is preserved even following complete ablation 11 or inactivation 12 of the auditory cortex in animals or extensive auditory lesions in humans 13,14 ; therefore, such tests are relatively uninformative about the existence of potential cortical-level dysfunction. Within the brainstem, NMDARs are involved primarily in complex processes involving plasticity and integration 15 . Such processes have been studied in schizophrenia to only a limited degree but may also be impaired 16 , suggesting that dysfunction occurs even at the brainstem level.…”

Specific synaptopathies diversify brain responses and hearing disorders: you lose the gain from early life

“…Both kainate and NMDA receptor subunits (NR1 and NR2A-D) have been described on the afferent post-synaptic density (for a review, see Puel et al 2002 ). In the adult system, an increase in glutamate release from IHCs has been shown to activate NMDA receptors and to trigger excessive Ca 2+ in SGN dendrites (Sanchez et al 2014 ). The resulting over-excitation increases ATP demand and correspondingly increases reactive oxygen species at IHC-SGN synapses (Sahley et al 2013 ).…”

Nonviral Reprogramming of Human Wharton's Jelly Cells Reveals Differences BetweenATOH1Homologues

“…S5) further supports the potential of development of a basic neuron phenotype in some cells as AMPA receptors are not present on hWJCs or hair cells, but are present on motor neurons. 82 In addition, all treated cells displayed positive presentation of MYO7A 1 day after transfection through immunocytochemistry; however, presentation of MYO7A decreased in groups transfected with MATH-1. MYO7A expression is expected if cells are differentiating toward a hair cell lineage, but HES5 expression is surprising because HES5 encourages support cell differentiation by negatively regulating ATOH1.…”