SummaryAging and acoustic trauma may result in partial peripheral deafferentation in the central auditory pathway of the mammalian brain. In accord with homeostatic plasticity, loss of sensory input results in a change in pre-and postsynaptic GABAergic and glycinergic inhibitory neurotransmission. As seen in development, age-related changes may be activity dependent. Age-related presynaptic changes in the cochlear nucleus include reduced glycine levels, while in the auditory midbrain and cortex, GABA synthesis and release are altered. Presumably, in response to age-related decreases in presynaptic release of inhibitory neurotransmitters, there are age-related postsynaptic subunit changes in the composition of the glycine (GlyR) and GABA A (GABA A R) receptors. Age-related changes in the subunit makeup of inhibitory pentameric receptor constructs result in altered pharmacological and physiological responses consistent with a net down-regulation of functional inhibition. Age-related functional changes associated with glycine neurotransmission in dorsal cochlear nucleus (DCN) include altered intensity and temporal coding by DCN projection neurons. Loss of synaptic inhibition in the superior olivary complex (SOC) and the inferior colliculus (IC) likely affect the ability of aged animals to localize sounds in their natural environment. Age-related postsynaptic GABA A R changes in IC and primary auditory cortex (A1) involve changes in the subunit makeup of GABA A Rs. In turn, these changes cause age-related changes in the pharmacology and response properties of neurons in IC and A1 circuits, which collectively may affect temporal processing and response reliability. Findings of age-related inhibitory changes within mammalian auditory circuits are similar to age and deafferentation plasticity changes observed in other sensory systems. Although few studies have examined sensory aging in the wild, these age-related changes would likely compromise an animal's ability to avoid predation or to be a successful predator in their natural environment.Key words: aging, central auditory system, GABA A receptor, glycine receptor, inhibitory neurotransmission, plasticity. THE JOURNAL OF EXPERIMENTAL BIOLOGY 1782important in determining the location of sound, echolocation and extracting information from voiced and unvoiced communication signals (Carr et al., 1986;Portfors and Wenstrup, 2001).The complex processing that occurs at the level of the MGB and the A1 is beyond the scope of the present review. Coding in the auditory cortex has been recently reviewed (Wang, 2007;Rauschecker, 2005). As seen in the visual cortex, in the auditory cortex, acoustically complex hierarchical analysis has been described for awake-behaving primates (Rauschecker, 2005;Steinschneider et al., 2008). A1 has been shown to undergo agerelated plastic changes, including down-regulation of inhibitory coding, similar to that observed at lower levels of the auditory pathway and in visual cortex. Similar to age-related changes, activity-dependant changes have be...

Fifteen to 35% of the United States population experiences tinnitus, a subjective "ringing in the ears". Up to 10 percent of those afflicted report severe and disabling symptoms. Tinnitus was induced in rats using unilateral, one-hour, 17 kHz-centered octave-band noise (116 dB SPL) and assessed using a gap-startle method. The dorsal cochlear nucleus (DCN) is thought to undergo plastic changes suggestive of altered inhibitory function during tinnitus development. Exposed rats showed near preexposure ABR thresholds for clicks and all tested frequencies 16 weeks post-exposure. Soundexposed rats showed significantly worse gap detection at 24 and 32 kHz 16 weeks following sound exposure, suggesting the development of chronic, high frequency tinnitus.Message and protein levels of α 1-3 , and β glycine receptor subunits (GlyRs), and the anchoring protein, gephyrin, were measured in DCN fusiform cells 4 months following sound exposure. Rats with evidence of tinnitus showed significant GlyR α 1 protein decreases in the middle and high frequency regions of the DCN while α 1 message levels were paradoxically increased. Gephyrin levels showed significant tinnitus-related increases in sound-exposed rats suggesting intracellular receptor trafficking changes following sound exposure. Consistent with decreased α 1 subunit protein levels, strychnine binding studies showed significant tinnitus-related decreases in the number of GlyR binding sites, supporting tinnitus-related changes in the number and/or composition of GlyRs.Collectively, these findings suggest the development of tinnitus is likely associated with functional GlyR changes in DCN fusiform cells consistent with previously described behavioral and neurophysiologic changes. Tinnitus related GlyR changes could provide a unique receptor target for tinnitus pharmacotherapy or blockade of tinnitus initiation. Keywordshearing loss; sound exposure; fusiform cell; auditory; glycine receptor; gephyrin Correspondence to: Dr. Donald M. Caspary, Phone: 217-545-2195, Fax: 217-545-0145, dcaspary@siumed.edu. Section Editor: Sensory Systems: Dr. Richard Weinberg, University of North Carolina, Department of Cell Biology and Anatomy, CB 7090, Chapel Hill, NC 27599, USA Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 December 1. Published in final edited form as:Neuroscience. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptTinnitus is a common audiologic complaint characterized by auditory perception without an external phys...

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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.

Tinnitus perception depends on the presence of its neural correlates within the auditory neuraxis and associated structures. Targeting specific circuits and receptors within the central nervous system in an effort to relieve the perception of tinnitus and its impact on one’s emotional and mental state has become a focus of tinnitus research. One approach is to upregulate endogenous inhibitory neurotransmitter levels (e.g. glycine and GABA) and selectively target inhibitory receptors in key circuits to normalize tinnitus pathophysiology. Thus, the basic functional and molecular properties of two major ligand-gated inhibitory receptor systems, the GABAA receptor (GABAAR) and glycine receptor (GlyR) are described. Also reviewed is the rationale for targeting inhibition which stems from reported tinnitus-related homeostatic plasticity of inhibitory neurotransmitter systems and associated enhanced neuronal excitability throughout most central auditory structures. However, the putative role of the medial geniculate body (MGB) in tinnitus has not been previously addressed, specifically in terms of its inhibitory afferents from inferior colliculus and thalamic reticular nucleus and its GABAAR functional heterogeneity. This heterogeneous population of GABAARs, which may be altered in tinnitus pathology, and its key anatomical position in the auditory CNS make the MGB a compelling structure for tinnitus research. Finally, some selective compounds, which enhance tonic inhibition, have successfully ameliorated tinnitus in animal studies, suggesting that the MGB and, to a lesser degree, the auditory cortex may be their primary locus of action. These pharmacological interventions are examined, in terms of their mechanism of action and why these agents, may be effective in tinnitus treatment.