Determination of the hydrogen-bond network and the ferrimagnetic structure of a rockbridgeite-type compound, [Formula: see text].

Applying neutron powder diffraction, four unique hydrogen positions were determined in a rockbridgeite-type compound, [Formula: see text] [Formula: see text]. Its honeycomb-like H-bond network running without interruption along the crystallographic [Formula: see text] axis resembles those in alkali sulphatic and arsenatic oxyhydroxides. They provide the so-called dynamically disordered H-bond network over which protons are superconducting in a vehicle mechanism. This is indicated by dramatic increases of dielectric constant and loss factor at room temperature. The relevance of static and dynamic disorder of OH and HOH groups are explained in terms of a high number of structural defects at octahedral chains alternatingly half-occupied by [Formula: see text] cations. The structure is built up by unusual octahedral doublet, triplet, and quartet clusters of aliovalent 3d transition metal cations, predicting complicate magnetic ordering and interaction. The ferrimagnetic structure below the Curie temperature [Formula: see text]-83 K could be determined from the structure analysis with neutron diffraction data at 25 K.

Anomalous dielectric response of short hydrogen bonds under pressure: the case of (Mn,Fe)2+AlPO4(OH)2H2O.

An anomalous increase in the real part of dielectric response is observed in Mn0.5Fe0.5AlPO4(OH)2H2O while cooling to ~70 K. This is addressed to field-induced proton dynamics in a short hydrogen bond of 2.480(3) Å. The absence of discontinuities in heat capacity curves above the Néel temperature (T N ≈ 7 K) excludes a paraelectric to antiferroelectric phase transition. Upon the application of mild hydrostatic pressures below 1.6 GPa, the maximum in the dielectric response is shifted from 70 K to lower temperatures near 2 K. This explains a narrow correlation between proton transfer and the compression of the short hydrogen bond length.

Adeno-associated virus-RNAi of GlyRα1 and characterization of its synapse-specific inhibition in OFF alpha transient retinal ganglion cells.

In the central nervous system, inhibition shapes neuronal excitation. In spinal cord glycinergic inhibition predominates, whereas GABAergic inhibition predominates in the brain. The retina uses GABA and glycine in approximately equal proportions. Glycinergic crossover inhibition, initiated in the On retinal pathway, controls glutamate release from presynaptic OFF cone bipolar cells (CBCs) and directly shapes temporal response properties of OFF retinal ganglion cells (RGCs). In the retina, four glycine receptor (GlyR) α-subunit isoforms are expressed in different sublaminae and their synaptic currents differ in decay kinetics. GlyRα1, expressed in both On and Off sublaminae of the inner plexiform layer, could be the glycinergic isoform that mediates On-to-Off crossover inhibition. However, subunit-selective glycine contributions remain unknown because we lack selective antagonists or cell class-specific subunit knockouts. To examine the role of GlyRα1 in direct inhibition in mature RGCs, we used retrogradely transported adeno-associated virus (AAV) that performed RNAi and eliminated almost all glycinergic spontaneous and visually evoked responses in PV5 (OFFα(Transient)) RGCs. Comparisons of responses in PV5 RGCs infected with AAV-scrambled-short hairpin RNA (shRNA) or AAV-Glra1-shRNA confirm a role for GlyRα1 in crossover inhibition in cone-driven circuits. Our results also define a role for direct GlyRα1 inhibition in setting the resting membrane potential of PV5 RGCs. The absence of GlyRα1 input unmasked a serial and a direct feedforward GABA(A)ergic modulation in PV5 RGCs, reflecting a complex interaction between glycinergic and GABA(A)ergic inhibition.

Optogenetic therapy for retinitis pigmentosa.

Retinitis pigmentosa (RP) refers to a diverse group of progressive, hereditary diseases of the retina that lead to incurable blindness and affect two million people worldwide. Artificial photoreceptors constructed by gene delivery of light-activated channels or pumps ('optogenetic tools') to surviving cell types in the remaining retinal circuit has been shown to restore photosensitivity in animal models of RP at the level of the retina and cortex as well as behaviorally. The translational potential of this optogenetic approach has been evaluated using in vitro studies involving post-mortem human retinas. Here, we review recent developments in this expanding field and discuss the potential and limitations of optogenetic engineering for the treatment of RP.

Vertical interactions across ten parallel, stacked representations in the mammalian retina.

The mammalian visual system analyses the world through a set of separate spatio-temporal channels. The organization of these channels begins in the retina, where the precise laminations of both the axon terminals of bipolar cells and the dendritic arborizations of ganglion cells suggests the presence of a vertical stack of neural strata at the inner plexiform layer (IPL). Conversely, many inhibitory amacrine cell classes are multiply or diffusely stratified, indicating that they might convey information between strata. On the basis of the diverse stratification and physiological properties of ganglion cells, it was suggested that the IPL contains a parallel set of representations of the visual world embodied in the strata and conveyed to higher centres by the classes of ganglion cells whose dendrites ramify at that stratum. Here we show that each stratum receives unique and substantively different excitatory and inhibitory neural inputs that are integrated to form at least ten different, parallel space-time spiking outputs. The response properties of these strata are ordered in the time domain. Inhibition through GABAC receptors extracts spatial edges in neural representations and seems to separate the functional properties of the strata. We describe a new form of neuronal interaction that we call 'vertical inhibition' that acts not laterally, but between strata.

Three levels of lateral inhibition: A space-time study of the retina of the tiger salamander.

The space-time patterns of activity generated across arrays of retinal neurons can provide a sensitive measurement of the effects of neural interactions underlying retinal activity. We measured the excitatory and inhibitory components associated with these patterns at each cellular level in the retina and further dissected inhibitory components pharmacologically. Using perforated and loose patch recording, we measured the voltages, currents, or spiking at 91 lateral positions covering approximately 2 mm in response to a flashed 300-microm-wide bar. First, we showed how the effect of well known lateral inhibition at the outer retina, mediated by horizontal cells, evolved in time to compress the spatial representation of the stimulus bar at ON and OFF bipolar cell bodies as well as horizontal cells. Second, we showed, for the first time, how GABA(C) receptor mediated amacrine cell feedback to bipolar terminals compresses the spatial representation of the stimulus bar at ON bipolar terminals over time. Third, we showed that a third spatiotemporal compression exists at the ganglion cell layer that is mediated by feedforward amacrine cells via GABA(A) receptors. These three inhibitory mechanisms, via three different receptor types, appear to compensate for the effects of lateral diffusion of activity attributable to dendritic spread and electrical coupling between retinal neurons. As a consequence, the width of the final representation at the ganglion cell level approximates the dimensions of the original stimulus bar.

Voltage-dependent uptake is a major determinant of glutamate concentration at the cone synapse: an analytical study.

It was suggested that glutamate concentration at the synaptic terminal of the cones was controlled primarily by a voltage-dependent glutamate transporter and that diffusion played a less important role. The conclusion was based on the observation that the rate of glutamate concentration during the hyperpolarizing light response was dramatically slowed when the transporter was blocked with dihydrokainate although diffusion remained intact. To test the validity of this notion we constructed a model in which the balance among uptake, diffusion, and release determined the flow of glutamate into and out of the synaptic cleft. The control of glutamate concentration was assumed here to be determined by two relationships; 1) glutamate concentration is the integral over the synaptic volume of the rates of release, uptake, and diffusion, and 2) membrane potential is the integral over the membrane capacitance of the dark, leak, and transporter-gated chloride current. These relationships are interdependent because glutamate uptake via the transporter is voltage dependent and because the transporter-gated current is concentration dependent. The voltage and concentration dependence of release and uptake, as well as the light-elicited, transporter-gated, and leak currents were measured in other studies. All of these measurements were incorporated into our predictive model of glutamate uptake. Our results show a good quantitative fit between the predicted and the measured magnitudes and rates of change of glutamate concentration, derived from the two interdependent relationships. This close fit supports the validity of these two relationships as descriptors of the mechanisms underlying the control of glutamate concentration, it verifies the accuracy of the experimental data from which the functions used in these relationships were derived, and it lends further support to the notion that glutamate concentration is controlled primarily by uptake at the transporter.

Response to change is facilitated by a three-neuron disinhibitory pathway in the tiger salamander retina.

Most retinal ganglion cells respond only transiently, for approximately 150 msec at the onset and termination of a light flash. The responses are transient because it has been shown that bipolar-to-ganglion cell transmission is truncated after 150 msec by a feedback inhibition to bipolar cell terminals. The feedback inhibition itself must be delayed by approximately 150 msec to allow the initial bipolar-ganglion cell transmission. This study identifies a three-component serial synaptic pathway from glycinergic amacrine cells to GABAergic amacrine cells to bipolar cell terminals as one source of this delay. We used perforated and whole-cell patch-clamp recordings to measure the timing of light responses in amacrine, bipolar, and ganglion cells under control and glycine and GABA receptor-blocked conditions. Our results suggest that, after a light flash, a population of glycinergic amacrine cells responds first, inhibiting a population of GABAergic amacrine cells for approximately 150 msec. The GABAergic amacrine cells feed back to bipolar terminals, but only after the 150 msec delay, allowing the bipolar terminals to excite ganglion cells for the first 150 msec. Blocking the glycinergic amacrine cell activity with strychnine allows the GABAergic system to become active earlier. GABAergic amacrine cells then inhibit release from bipolar cells earlier. Under these conditions, the ganglion cell response to change would be decreased.

Postsynaptic response kinetics are controlled by a glutamate transporter at cone photoreceptors.

We evaluated the role of the sodium/glutamate transporter at the synaptic terminals of cone photoreceptors in controlling postsynaptic response kinetics. The strategy was to measure the changes in horizontal cell response rate induced by blocking transporter uptake in cones with dihydrokainate (DHK). DHK was chosen as the uptake blocker because, as we show through autoradiographic uptake measurements, DHK specifically blocked uptake in cones without affecting uptake in Mueller cells. Horizontal cells depolarized from about -70 to -20 mV as the exogenous glutamate concentration was increased from approximately 1 to 40 microM, so horizontal cells can serve as "glutamate electrodes" during the light response. DHK slowed the rate of hyperpolarization of the horizontal cells in a dose-dependent way, but didn't affect the kinetics of the cone responses. At 300 microM DHK, the rate of the horizontal cell hyperpolarization was slowed to only 17 +/- 8.5% (mean +/- SD) of control. Translating this to changes in glutamate concentration using the slice dose response curve as calibration in Fig. 2, DHK reduced the rate of removal of glutamate from approximately 0.12 to 0.031 microM/s. The voltage dependence of uptake rate in the transporter alone was capable of modulating glutamate concentration: we blocked vesicular released glutamate with bathed 20 mM Mg2+ and then added 30 microM glutamate to the bath to reestablish a physiological glutamate concentration level at the synapse and thereby depolarize the horizontal cells. Under these conditions, a light flash elicited a 17-mV hyperpolarization in the horizontal cells. When we substituted kainate, which is not transported, for glutamate, horizontal cells were depolarized but light did not elicit any response, indicating that the transporter alone was responsible for the removal of glutamate under these conditions. This suggests that the transporter was both voltage dependent and robust enough to modulate glutamate concentration. The transporter must be at least as effective as diffusion in removing glutamate from the synapse because there is only a very small light response once the transporter is blocked. The transporter, via its voltage dependence on cone membrane potential, appears to contribute significantly to the control of postsynaptic response kinetics.