Targeting inhibitory neurotransmission in tinnitus

Abstract

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.

Impairments of thalamic resting-state functional connectivity in patients with chronic tinnitus

“…The thalamus, which regulates the flow of sensory information to and from the auditory cortex, is thought to play an important role in the perception of tinnitus [9,14]. Consistent with this view, we observed that the thalamus showed decreased functional connectivity with the primary and associative auditory cortex, specifically the STG (Brodmann's area 42) and MTG (Brodmann's area 21).…”

“…However, the mechanisms responsible for these functional changes are unknown, but could involve aberrant inhibition [9]. Hypothetically, impaired thalamic gating could directly affect the function of the auditory cortex or alternatively alter the function of subcortical regions.…”

“…Spontaneous activity of MGB neurons are altered by ototoxic drugs that induce tinnitus [8]. Disrupted inhibitory neurotransmission between the thalamus and other CNS regions such as the inferior colliculus and auditory cortex may also contribute to tinnitus [9]. MRI studies have identified structural and functional abnormalities in the thalamus of tinnitus patients.…”

Analysis of Hyperekplexia Mutations Identifies Transmembrane Domain Rearrangements That Mediate Glycine Receptor Activation

“…Several pLGIC receptors, notably the nicotinic acetylcholine receptor and the GABA A receptor (GABA A R), have long been important therapeutic targets, and the GlyR has recently emerged as a potential target for indications including inflammatory pain sensitization (10 -12), opioid-induced breathing depression (13), tinnitus (14), and temporal lobe epilepsy (15). It is important to resolve the mechanisms by which the structure of pLGIC receptors changes between the closed and open states to design new drugs that bias the receptor toward the desired conformation.…”

Pharmacodynamics of potassium channel openers in cultured neuronal networks

“…Firstly, other conventional tinnitus inducers such as salicylate or quinine had a postulated convergent mechanism that either directly or indirectly targeted the GABAergic inhibitory interneuron of the afferent pathway in the auditory cortex, resulting in disrupted plasticity of excitation-inhibition and resulting hyperactivity (Noreña et al, 2010). In addition, it should be noted that age-related tinnitus co-exhibited decreased inhibitory neurotransmission in the auditory cortex and along the auditory subcortical pathway (Caspary et al, 2013;Richardson et al, 2012). We used a simplified cortical disinhibition model with the GABA A antagonist pentylenetetrazol.…”