Is GABA neurotransmission enhanced in auditory thalamus relative to inferior colliculus?

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central auditory system. Sensory thalamic structures show high levels of non-desensitizing extrasynaptic GABAA receptors (GABAARs) and a reduction in the redundancy of coded information. The present study compared the inhibitory potency of GABA acting at GABAARs between the inferior colliculus (IC) and the medial geniculate body (MGB) using quantitative in vivo, in vitro, and ex vivo experimental approaches. In vivo single unit studies compared the ability of half maximal inhibitory concentrations of GABA to inhibit sound-evoked temporal responses, and found that GABA was two to three times (P < 0.01) more potent at suppressing MGB single unit responses than IC unit responses. In vitro whole cell patch-clamp slice recordings were used to demonstrate that gaboxadol, a δ-subunit selective GABAAR agonist, was significantly more potent at evoking tonic inhibitory currents from MGB neurons than IC neurons (P < 0.01). These electrophysiological findings were supported by an in vitro receptor binding assay which used the picrotoxin analog [(3)H]TBOB to assess binding in the GABAAR chloride channel. MGB GABAARs had significantly greater total open chloride channel capacity relative to GABAARs in IC (P < 0.05) as shown by increased total [(3)H]TBOB binding. Finally, a comparative ex vivo measurement compared endogenous GABA levels and suggested a trend towards higher GABA concentrations in MGB than in IC. Collectively, these studies suggest that, per unit GABA, high affinity extrasynaptic and synaptic GABAARs confer a significant inhibitory GABAAR advantage to MGB neurons relative to IC neurons. This increased GABA sensitivity likely underpins the vital filtering role of auditory thalamus.

Reduced GABA(A) receptor-mediated tonic inhibition in aged rat auditory thalamus.

Age-related deficits in detecting and understanding speech, which can lead to social withdrawal and isolation, have been linked to changes in the central auditory system. Many of these central age-related changes involve altered mechanisms of inhibitory neurotransmission, essential for accurate and reliable auditory processing. In sensory thalamus, GABA mediates fast (phasic) inhibition via synaptic GABA(A) receptors (GABA(A)Rs) and long-lasting (tonic) inhibition via high-affinity (extrasynaptic) GABA(A)Rs, which provide a majority of the overall inhibitory tone in sensory thalamus. Due to a delicate balance between excitation and inhibition, alteration of normal thalamic inhibitory function with age and a reduction of tonic GABA(A)R-mediated inhibition may disrupt normal adult auditory processing, sensory gating, thalamocortical rhythmicity, and slow-wave sleep. The present study examines age-related homeostatic plasticity of GABA(A)R function in auditory thalamus or the medial geniculate body (MGB). Using thalamic slices from young adult (3-8 months) and aged (28-32 months) rats, these studies found a 45.5% reduction in GABA(A)R density and a 50.4% reduction in GABA(A)R-mediated tonic whole cell Cl(-) currents in the aged MGB. Synaptic GABA(A)R-mediated inhibition appeared differentially affected in aged lemniscal and nonlemniscal MGB. Except for resting membrane potential, basic properties were unaltered with age, including neuronal Cl(-) homeostasis determined using the gramicidin perforated patch-clamp method. Results demonstrate selective significant age-dependent deficits in the tonic inhibitory tone within the MGB. These data suggest that selective GABA(A)R subtype agonists or modulators might be used to augment MGB inhibitory neurotransmission, improving speech understanding, sensory gating, and slow-wave sleep for a subset of elderly individuals.

Age-related GABAA receptor changes in rat auditory cortex.

Auditory cortex (AI) shows age-related decreases in pre-synaptic markers for gamma-aminobutyric acid (GABA) and degraded AI neuronal response properties. Previous studies find age-related increases in spontaneous and driven activity, decreased spectral and directional sensitivity, and impaired novelty detection. The present study examined expression of GABA(A) receptor (GABA(A)R) subunit message, protein, and quantitative GABA(A)R binding in young, middle-aged, and aged rat AI, with comparisons with adjoining parietal cortex. Significant loss of GABA(A)R α(1) subunit message across AI layers was observed in middle-aged and aged rats and α(1) subunit protein levels declined in layers II and III. Age-related increases in GABA(A)R α(3) subunit message and protein levels were observed in certain AI layers. GABA(A)R subunits, including ß(1), ß(2), γ(1), γ(2s), and γ(2L), primarily, but not exclusively, showed age-related declines at the message and protein levels. The ability of GABA to modulate [(3)H]t-butylbicycloorthobenzoate binding in the chloride channel showed age-related decreases in peak binding and changes in desensitization kinetics. Collectively, age-related changes in GABA(A)R subunit composition would alter the magnitude and temporal properties of inhibitory synaptic transmission and could underpin observed age-related functional changes seen in the elderly.

Targeting inhibitory neurotransmission in tinnitus.

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 GABA(A) receptor (GABA(A)R) 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 GABA(A)R functional heterogeneity. This heterogeneous population of GABA(A)Rs, 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. This article is part of a Special Issue entitled: Tinnitus Neuroscience.

Extrasynaptic GABA(A) receptors and tonic inhibition in rat auditory thalamus.

BACKGROUND: Neural inhibition plays an important role in auditory processing and attentional gating. Extrasynaptic GABA(A) receptors (GABA(A)R), containing α(4)and δ GABA(A)R subunits, are thought to be activated by GABA spillover outside of the synapse following release resulting in a tonic inhibitory Cl(-) current which could account for up to 90% of total inhibition in visual and somatosensory thalamus. However, the presence of this unique type of inhibition has not been identified in auditory thalamus. METHODOLOGY/PRINCIPAL FINDINGS: The present study used gaboxadol, a partially selective potent agonist for δ-subunit containing GABA(A) receptor constructs to elucidate the presence of extrasynaptic GABA(A)Rs using both a quantitative receptor binding assay and patch-clamp electrophysiology in thalamic brain slices. Intense [(3)H]gaboxadol binding was found to be localized to the MGB while whole cell recordings from MGB neurons in the presence of gaboxadol demonstrated the expression of δ-subunit containing GABA(A)Rs capable of mediating a tonic inhibitory Cl(-) current. CONCLUSIONS/SIGNIFICANCE: Potent tonic inhibitory GABA(A)R responses mediated by extrasynaptic receptors may be important in understanding how acoustic information is processed by auditory thalamic neurons as it ascends to auditory cortex. In addition to affecting cellular behavior and possibly neurotransmission, functional extrasynaptic δ-subunit containing GABA(A)Rs may represent a novel pharmacological target for the treatment of auditory pathologies including temporal processing disorders or tinnitus.