Intracellular sterol dynamics

We review the cellular mechanisms implicated in cholesterol trafficking and distribution. Recent studies have provided new information about the distribution of sterols within cells, including analysis of its transbilayer distribution. The cholesterol interaction with other lipids and its engagement in various trafficking processes will determine its proper level in a specific membrane; making the cholesterol distribution uneven among the various intracellular organelles. The cholesterol content is important since cholesterol plays an essential role in membranes by controlling their physicochemical properties as well as key cellular events such as signal transduction and protein trafficking. Cholesterol movement between cellular organelles is highly dynamic, and can be achieved by vesicular and non-vesicular processes. Various studies have analyzed the proteins that play a significant role in these processes, giving us new information about the relative importance of these two trafficking pathways in cholesterol transport. Although still poorly characterized in many trafficking routes, several potential sterol transport proteins have been described in detail; as a result, molecular mechanisms for sterol transport among membranes start to be appreciated.     

Role of hyperpolarization-activated conductances in the lateral superior olive: A modeling study

This modeling study examines the possible functional roles of two hyperpolarization-activated conductances in lateral superior olive (LSO) principal neurons. Inputs of these LSO neurons are transformed into an output, which provides a firing-rate code for a certain interaural sound intensity difference (IID) range. Recent experimental studies have found pharmacological evidence for the presence of both the Gh conductance as well as the inwardly rectifying outward GKIR conductance in the LSO. We addressed the question of how these conductances influence the dynamic range (IID versus firing rate). We used computer simulations of both a point-neuron model and a two-compartmental model to investigate this issue, and to determine the role of these conductances in setting the dynamic range of these neurons. The width of the dynamic regime, the frequency-current (f-I) function, first-spike latency, subthreshold oscillations and the interplay between the two hyperpolarization activated conductances are discussed in detail. The in vivo non-monotonic IID-firing rate function in a subpopulation of LSO neurons is in good correspondence with our simulation predictions. Two compartmental model simulation results suggest segregation of Gh and GKIR conductances on different compartments, as this spatial configuration could explain certain experimental results.     

Glutamate co-transmission from developing medial nucleus of the trapezoid body--lateral superior olive synapses is cochlear dependent in kanamycin-treated rats

Cochlear dependency of glutamate co-transmission at the medial nucleus of the trapezoid body (MNTB) – the lateral superior olive (LSO) synapses was investigated using developing rats treated with high dose kanamycin. Rats were treated with kanamycin from postnatal day (P) 3 to P8. A scanning electron microscopic study on P9 demonstrated partial cochlear hair cell damage. A whole cell voltage clamp experiment demonstrated the increased glutamatergic portion of postsynaptic currents (PSCs) elicited by MNTB stimulation in P9–P11 kanamycin-treated rats. The enhanced VGLUT3 immunoreactivities (IRs) in kanamycin-treated rats and asymmetric VGLUT3 IRs in the LSO of unilaterally cochlear ablated rats supported the electrophysiologic data. Taken together, it is concluded that glutamate co-transmission is cochlear-dependent and enhanced glutamate co-transmission in kanamycin-treated rats is induced by partial cochlear damage.     

Glycine-induced currents are insensitive to the glycine receptor α1 subunit-specific blocker, cyanotriphenylborate, in older circling mice

The pharmacologic characteristics of glycine receptors (GlyRs) in the lateral superior olive (LSO) of circling mice, animal model for inherited deafness, were investigated using a GlyR α₁ subunit-specific receptor blocker (cyanotriphenylborate [CTB]). There was a statistically significant age-dependent increase in the antagonistic effect of CTB in heterozygous (+/cir) mice. In postnatal (P)0–P3 heterozygous (+/cir) mice, glycine currents evoked by glycine puffs were reduced to 20.4 ± 2.6, 37.1 ± 3.1, and 63.9 ± 2.5% at 0.1, 1, and 10 μM CTB (n = 13) compared to controls, while the glycine currents were reduced to 22.3 ± 3.5, 52.9 ± 4.1, and 78.3 ± 3.5% at 0.1, 1, and 10 μM CTB (n = 7) in P8–P12 heterozygous (+/cir) mice. In contrast, the antagonistic effect of CTB was not strong and even less than that of younger animals in older homozygous (cir/cir) mice. In P0–P3 homozygous (cir/cir) mice, the extent of inhibition was 20.2 ± 3.7, 37.8 ± 4.3, and 66.8 ± 4.2% at 0.1, 1, and 10 μM CTB (n = 6) compared to controls, while the extent of inhibition was 18.7 ± 2.4, 28.1 ± 3.9, and 39.1 ± 8.2% (n = 6) in P8–P12 homozygous (cir/cir) mice. The age-dependent decrease in the antagonistic effect of CTB indicates the abnormal development of the α₁ subunit-containing GlyRs in homozygous (cir/cir) mice.     

Chemical neuroprotection in the cochlea: the modulation of dopamine release from lateral olivocochlear efferents

The prevalence of sensorineural hearing loss is increasing worldwide, mainly due to ageing, increased noise exposure and cardiovascular risk factors. Several papers dealt with the mechanisms underlying the primary causes of impaired hearing and eventual deafness, including the damage and loss of auditory hair cells; however, very little is known about the protective mechanisms that exist for hearing. Several recent investigations have implicated dopamine (DA) in a neuroprotective circuit for the cochlea. The lateral olivocochlear (LOC) efferents provide axonal innervation of the inner hair cell afferent synapses and release DA and other substances in response to different stimuli. Under ischemic conditions or during noise exposure, DA has been proven to play a neuroprotective role against glutamate excitotoxicity. This review summarises what is currently known about the modulation of DA release in the cochlea, using primarily in vitro experimental data. Based on recent knowledge, there could be two functional subgroups within the LOC fibres, i.e., the DA- and GABA-containing projections. In this review, we attempt to show the neurochemical interactions between these two subsystems. Other aspects of cochlear neurotransmission are also discussed to provide a complete picture of cochlear dopaminergic function in physiological and pathophysiological cases with particular reference to excitotoxicity.