What's the buzz? The neuroscience and the treatment of tinnitus.

Tinnitus is a pervasive public health issue that affects ∼15% of the United States population. Similar estimates have also been shown on a global scale, with similar prevalence found in Europe, Asia, and Africa. The severity of tinnitus is heterogeneous, ranging from mildly bothersome to extremely disruptive. In the United States, ∼10-20% of individuals who experience tinnitus report symptoms that severely reduce their quality of life. Due to the huge personal and societal burden, in the last 20 yr a concerted effort on basic and clinical research has significantly advanced our understanding and treatment of this disorder. Yet, neither full understanding, nor cure exists. We know that tinnitus is the persistent involuntary phantom percept of internally generated nonverbal indistinct noises and tones, which in most cases is initiated by acquired hearing loss and maintained only when this loss is coupled with distinct neuronal changes in auditory and extra-auditory brain networks. Yet, the exact mechanisms and patterns of neural activity that are necessary and sufficient for the perceptual generation and maintenance of tinnitus remain incompletely understood. Combinations of animal model and human research will be essential in filling these gaps. Nevertheless, the existing progress in investigating the neurophysiological mechanisms has improved current treatment and highlighted novel targets for drug development and clinical trials. The aim of this review is to thoroughly discuss the current state of human and animal tinnitus research, outline current challenges, and highlight new and exciting research opportunities.

A role for cAMP in long-term depression at hippocampal mossy fiber synapses.

Mossy fiber synapses on hippocampal CA3 pyramidal cells, in addition to expressing an NMDA receptor-independent form of long-term potentiation (LTP), have recently been shown to express a novel presynaptic form of long-term depression (LTD). We have studied the mechanisms underlying mossy fiber LTD and present evidence that it is triggered, at least in part, by a metabotropic glutamate receptor-mediated decrease in adenylyl cyclase activity, which leads to a decrease in the activity of the cAMP-dependent protein kinase (PKA) and a reversal of the presynaptic processes responsible for mossy fiber LTP. The bidirectional control of synaptic strength at mossy fiber synapses by activity therefore appears to be due to modulation of the cAMP-PKA signaling pathway in mossy fiber boutons.

Induction of endogenous channels by high levels of heterologous membrane proteins in Xenopus oocytes.

Xenopus oocytes are widely employed for heterologous expression of cloned proteins, particularly electrogenic molecules such as ion channels and transporters. The high levels of expression readily obtained permit detailed investigations without interference from endogenous conductances. Injection of min K mRNA into Xenopus oocytes results in expression of voltage-dependent potassium-selective channels. Recent data show that injections of high concentrations of min K mRNA also induce a chloride current with very different biophysical, pharmacological, and regulatory properties from the min K potassium current. This led to the suggestion that the min K protein acts as an inducer of endogenous, normally silent oocyte ion channels. We now report that high levels of heterologous expression of many membrane proteins in Xenopus oocytes specifically induce this chloride current and a hyperpolarization-activated cation-selective current. The current is blocked by 4,4'-diisothiocyanostilbene-2-2'-disulphonic acid and tetraethylammonium, enhanced by clofilium, and is pH-sensitive. Criteria are presented that distinguish this endogenous current from those due to heterologous expression of electrogenic proteins in Xenopus oocytes. Together with structure-function studies, these results support the hypothesis that the min K protein comprises a potassium-selective channel.

Gating of I(sK) channels expressed in Xenopus oocytes.

The channel underlying the slow component of the voltage-dependent delayed outward rectifier K+ current, I(Ks), in heart is composed of the minK and KvLQT1 proteins. Expression of the minK protein in Xenopus oocytes results in I(Ks)-like currents, I(sK), due to coassembly with the endogenous XKvLQT1. The kinetics and voltage-dependent characteristics of I(sK) suggest a distinct mechanism for voltage-dependent gating. Currents recorded at 40 mV from holding potentials between -60 and -120 mV showed an unusual "cross-over," with the currents obtained from more depolarized holding potentials activating more slowly and deviating from the Cole-Moore prediction. Analysis of the current traces revealed two components with fast and slow kinetics that were not affected by the holding potential. Rather, the relative contribution of the fast component decreased with depolarized holding potentials. Deactivation and reactivation, after a short period of repolarization (100 ms), was markedly faster than the fast component of activation. These gating properties suggest a physiological mechanism by which cardiac I(Ks) may suppress premature action potentials.

min K channels form by assembly of at least 14 subunits.

Injection of min K mRNA into Xenopus oocytes results in expression of slowly activating voltage-dependent potassium channels, distinct from those induced by expression of other cloned potassium channels. The min K protein also differs in structure, containing only a single predicted transmembrane domain. While it has been demonstrated that all other cloned potassium channels form by association of four independent subunits, the number of min K monomers which constitute a functional channel is unknown. In rat min K, replacement of Ser-69 by Ala (S69A) causes a shift in the current-voltage (I-V) relationship to more depolarized potentials; currents are not observed at potentials negative to 0 mV. To determine the subunit stoichiometry of min K channels, wild-type and S69A subunits were coexpressed. Injections of a constant amount of wild-type mRNA with increasing amounts of S69A mRNA led to potassium currents of decreasing amplitude upon voltage commands to -20 mV. Applying a binomial distribution to the reduction of current amplitudes as a function of the different coinjection mixtures yielded a subunit stoichiometry of at least 14 monomers for each functional min K channel. A model is presented for how min K subunits may form a channel.

Rab3A is essential for mossy fibre long-term potentiation in the hippocampus.

Repetitive activation of excitatory synapses in the central nervous system results in a long-lasting increase in synaptic transmission called long-term potentiation (LTP). It is generally believed that this synaptic plasticity may underlie certain forms of learning and memory. LTP at most synapses involves the activation of the NMDA (N-methyl-D-aspartate) subtype of glutamate receptor, but LTP at hippocampal mossy fibre synapses is independent of NMDA receptors and has a component that is induced and expressed presynaptically. It appears to be triggered by a rise in presynaptic Ca2+, and requires the activation of protein kinase A, which leads to an increased release of glutamate. A great deal is known about the biochemical steps involved in the vesicular release of transmitter, but none of these steps has been directly implicated in long-term synaptic plasticity. Here we show that, although a variety of short-term plasticities are normal, LTP at mossy fibre synapses is abolished in mice lacking the synaptic vesicle protein Rab3A.