Age-related changes in glycine receptor subunit composition and binding in dorsal cochlear nucleus

Abstract

Age-related hearing loss, presbycusis, can be thought of, in part, as a slow progressive peripheral deafferentation. Previous studies suggest that certain deficits seen in presbycusis may partially result from functional loss of the inhibitory neurotransmitter glycine in dorsal cochlear nucleus (DCN). The present study assessed age-related behavioral gap detection changes and neurochemical changes of postsynaptic glycine receptor (GlyRs) subunits and their anchoring protein gephyrin in fusiform cells of young (7-11 month) and aged (28-33 month) Fischer Brown Norway (FBN) rats. Aged rats showed significantly (20-30 dB) elevated auditory brainstem-evoked response thresholds across all tested frequencies and worse gap detection ability compared to young FBN rats. In situ hybridization and quantitative immunocytochemistry were used to measure GlyR subunit message and protein levels. There were significant age-related increases in the α1 subunit message with significant age-related decreases in α1 subunit protein. Gephyrin message and protein showed significant increases in aged DCN fusiform cells. The pharmacologic consequences of these age-related subunit changes were assessed using [3H] strychnine binding. In support of the age-related decrease of α1 subunit protein levels in DCN, there was a significant age-related decrease in the total number of GlyR binding sites with no significant change in affinity. These age-related changes may reflect an effort to re-establish a homeostatic balance between excitation and inhibition impacting on DCN fusiform cells by down-regulation of inhibitory function in the face of an age-related loss of peripheral input. Age-related decrease in presynaptic glycine release results in altered subunit composition and this may correlate with loss of temporal coding of the aged fusiform cell in DCN. The previously reported role for gephyrin in retrograde intracellular receptor subunit trafficking could contribute to the α1 decrease in the face of increased message.

Timing is everything: Temporal processing deficits in the aged auditory brainstem

“…When glycinergic receptors are blocked using strychnine, vector strength is reduced in FCs (Backoff et al, 1997). Thus, the present results suggest that an age-related alteration glycinergic neurotransmission may play a role in the etiology of age-related changes in response to SAM stimuli in the DCN (Backoff et al, 1999;Wang et al, 2009). …”

Proposed comprehensive ototoxicity monitoring program for VA healthcare (COMP-VA)

“…These problems can influence the ability of an individual to understand speech and obtain benefit from hearing aids. Further, a growing body of literature suggests that peripheral hearing loss leads over time to major changes in auditory brainstem structures and neurochemistry-changes that have been linked to impaired auditory temporal processing in animal models [35][36][37]. While it is difficult to determine using clinical methods the extent that frequency tuning, perceptual loudness growth, and temporal processing are impaired, it is clear that the speech signal processed by a hearing aid and then an impaired ear can be substantially degraded.…”

Cellular Mechanisms of Age-Related Hearing Loss

“…Age-related decreases in glycine (Willott et al 1997 ), inhibitory amino acid synaptic vesicle transporters ( Fig. 15.5 ) (Alvarado et al 2014 ), and synaptic release of glycine (Xie and Manis 2013 ) are mirrored by changes in postsynaptic GlyR subunit expression and composition and altered glycine binding to GlyR (Willott et al 1997 ;Caspary et al 2008 ;Wang et al 2009 ). Briefl y, at the synaptic level, glycinergic inhibition decreases with age (Xie and Manis 2013 ).…”