Can GABAkines Quiet the Noise? The GABAA Receptor Neurobiology and Pharmacology of Tinnitus

Overexposure to intense sound can cause temporary or permanent hearing loss. Postexposure recovery of threshold sensitivity has been assumed to indicate reversal of damage to delicate mechano-sensory and neural structures of the inner ear and no persistent or delayed consequences for auditory function. Here, we show, using cochlear functional assays and confocal imaging of the inner ear in mouse, that acoustic overexposures causing moderate, but completely reversible, threshold elevation leave cochlear sensory cells intact, but cause acute loss of afferent nerve terminals and delayed degeneration of the cochlear nerve. Results suggest that noise-induced damage to the ear has progressive consequences that are considerably more widespread than are revealed by conventional threshold testing. This primary neurodegeneration should add to difficulties hearing in noisy environments, and could contribute to tinnitus, hyperacusis, and other perceptual anomalies commonly associated with inner ear damage.

This mini-review attempts to update experimental evidence on the existence of GABA(A) receptor pharmacological subtypes and to produce a list of those native receptors that exist. GABA(A) receptors are chloride channels that mediate inhibitory neurotransmission. They are members of the Cys-loop pentameric ligand-gated ion channel (LGIC) superfamily and share structural and functional homology with other members of that family. They are assembled from a family of 19 homologous subunit gene products and form numerous receptor subtypes with properties that depend upon subunit composition, mostly hetero-oligomeric. These vary in their regulation and developmental expression, and importantly, in brain regional, cellular, and subcellular localization, and thus their role in brain circuits and behaviors. We propose several criteria for including a receptor hetero-oligomeric subtype candidate on a list of native subtypes, and a working GABA(A) receptor list. These criteria can be applied to all the members of the LGIC superfamily. The list is divided into three categories of native receptor subtypes: "Identified", "Existence with High Probability", and "Tentative", and currently includes 26 members, but will undoubtedly grow, with future information. This list was first presented by Olsen & Sieghart (in press).

The GABA(A) receptors are the major inhibitory neurotransmitter receptors in mammalian brain. Each isoform consists of five homologous or identical subunits surrounding a central chloride ion-selective channel gated by GABA. How many isoforms of the receptor exist is far from clear. GABA(A) receptors located in the postsynaptic membrane mediate neuronal inhibition that occurs in the millisecond time range; those located in the extrasynaptic membrane respond to ambient GABA and confer long-term inhibition. GABA(A) receptors are responsive to a wide variety of drugs, e.g. benzodiazepines, which are often used for their sedative/hypnotic and anxiolytic effects.