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The ability to control and modulate the action potential firing in neurons represents a powerful tool for neuroscience research and clinical applications. While neuronal excitation has been achieved with many tools, including electrical and optical stimulation, hyperpolarization and neuronal inhibition are typically obtained through patch-clamp or optogenetic manipulations. Here we report the use of conjugated polymer films interfaced with neurons for inducing a light-mediated inhibition of their electrical activity. We show that prolonged illumination of the interface triggers a sustained hyperpolarization of the neuronal membrane that significantly reduces both spontaneous and evoked action potential firing. We demonstrate that the polymeric interface can be activated by either visible or infrared light and is capable of modulating neuronal activity in brain slices and explanted retinas. These findings prove the ability of conjugated polymers to tune neuronal firing and suggest their potential application for the in-vivo modulation of neuronal activity.

An overview of the optical methods available to modulate the cellular activity in cell cultures and biological tissues is presented, with a focus on the use of exogenous functional materials that absorb electromagnetic radiation and transduce it into a secondary stimulus for cell excitation, with high temporal and spatial resolution. Both organic and inorganic materials are critically evaluated, for in vitro and in vivo applications. Finally, as a direct practical application of optical-stimulation techniques, the most recent results in the realization of artificial visual implants are discussed., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Transcatheter valve-in-valve (VIV) implantation evolved as a therapeutic alternative, despite an increased risk of coronary obstruction in comparison with a regular transcatheter aortic valve implantation (TAVI). We report a comprehensive single-institution experience emphasizing strategies to reduce the risk of myocardial ischemia., Methods: Since 2009, 639 patients underwent a TAVI procedure in our institution. All patients are prospectively collected into an institutional registry. In total 31 patients underwent a VIV procedure at our institution (age 77.8 ± 6.3 years; The Society or Thoracic Surgeons predicted risk of mortality 20.9% ± 8.8%; New York Heart Association (NYHA) 3.0 ± 0.6). Degenerated bioprostheses included 24 Mitroflow, 6 Edwards Perimount, and Cryo-Valve O' Brien with label sizes from 21 to 27 mm. The type of failure was mostly regurgitation with or without concomitant stenosis (78%)., Results: Patients were provided with 5 Medtronic CoreValves, 15 Edwards SapienXT, 1 Edwards Sapien 3, 7 Medtronic Engager, and 3 Symetis Acurate TA valves. The procedural success rate was 88%. The left main stem was occluded in 1 patient (Sapien XT 26 in a Mitroflow 25 mm) who underwent emergent revascularization. Two patients suffering from a degenerated Mitroflow prosthesis needed a second valve (Sapien XT). Two patients with a degenerated Mitroflow prosthesis treated with a Sapien XT developed postprocedural myocardial ischemia and deceased on postoperative days 1 and 2, accounting to an overall incidence of coronary insufficiency associated to the VIV procedure of 10%. With the introduction of valves allowing commissural alignment (Acurate TA) and leaflet capturing as well (Engager) no further coronary insufficiency occurred. The mean gradient decreased significantly from 39.3 ± 14.0 to 16.1 ± 7.2 mm Hg (p = 0.002). Post-procedural regurgitation was classified as trace in 7 patients (23%) and moderate in 4 patients (13%). The 30-day survival was 77% with a significantly improved NYHA class of 1.79 ± 0.58 (p = 0.001)., Conclusions: Jeopardizing coronary blood flow is likely in stenotic and calcified bioprostheses, particularly in tubelike aortic sinuses. Planning, imaging, and the use of valves allowing commissural alignment as well as leaflet capturing seem to reduce the risk. Further studies are necessary to support this hypothesis., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Zebrafish is becoming an increasingly popular model in the field of visual neuroscience. Although the absorption spectra of its cone photopigments have been described, the cone action spectra were still unknown. In this study we report the action spectra of the four types of zebrafish cone photoreceptors, determined by measuring voltage responses upon light stimulation using whole cell patch clamp recordings. A generic template of photopigment absorption spectra was fit to the resulting action spectra in order to establish the maximum absorption wavelength, the A2-based photopigment contribution and the size of the β-wave of each cone-type. Although in general there is close correspondence between zebrafish cone action- and absorbance spectra, our data suggest that in the case of MWS- and LWS-cones there is appreciable contribution of A2-based photopigments and that the β-wave for these cones is smaller than expected based on the absorption spectra.

In neuronal systems, excitation and inhibition must be well balanced to ensure reliable information transfer. The cone/horizontal cell (HC) interaction in the retina is an example of this. Because natural scenes encompass an enormous intensity range both in temporal and spatial domains, the balance between excitation and inhibition in the outer retina needs to be adaptable. How this is achieved is unknown. Using electrophysiological techniques in the isolated retina of the goldfish, it was found that opening Ca(2+)-dependent Cl(-) channels in recorded cones reduced the size of feedback responses measured in both cones and HCs. Furthermore, we show that cones express Cl(-) channels that are gated by GABA released from HCs. Similar to activation of I(Cl(Ca)), opening of these GABA-gated Cl(-) channels reduced the size of light-induced feedback responses both in cones and HCs. Conversely, application of picrotoxin, a blocker of GABA(A) and GABA(C) receptors, had the opposite effect. In addition, reducing GABA release from HCs by blocking GABA transporters also led to an increase in the size of feedback. Because the independent manipulation of Ca(2+)-dependent Cl(-) currents in individual cones yielded results comparable to bath-applied GABA, it was concluded that activation of either Cl(-) current by itself is sufficient to reduce the size of HC feedback. However, additional effects of GABA on outer retinal processing cannot be excluded. These results can be accounted for by an ephaptic feedback model in which a cone Cl(-) current shunts the current flow in the synaptic cleft. The Ca(2+)-dependent Cl(-) current might be essential to set the initial balance between the feedforward and the feedback signals active in the cone HC synapse. It prevents that strong feedback from HCs to cones flood the cone with Ca(2)(+). Modulation of the feedback strength by GABA might play a role during light/dark adaptation, adjusting the amount of negative feedback to the signal to noise ratio of the cone output.

Background: Recent studies designed to identify the mechanism by which retinal horizontal cells communicate with cones have implicated two processes. According to one account, horizontal cell hyperpolarization induces an increase in pH within the synaptic cleft that activates the calcium current (Ca(2+)-current) in cones, enhancing transmitter release. An alternative account suggests that horizontal cell hyperpolarization increases the Ca(2+)-current to promote transmitter release through a hemichannel-mediated ephaptic mechanism., Methodology/principal Findings: To distinguish between these mechanisms, we interfered with the pH regulating systems in the retina and studied the effects on the feedback responses of cones and horizontal cells. We found that the pH buffers HEPES and Tris partially inhibit feedback responses in cones and horizontal cells and lead to intracellular acidification of neurons. Application of 25 mM acetate, which does not change the extracellular pH buffer capacity, does lead to both intracellular acidification and inhibition of feedback. Because intracellular acidification is known to inhibit hemichannels, the key experiment used to test the pH hypothesis, i.e. increasing the extracellular pH buffer capacity, does not discriminate between a pH-based feedback system and a hemichannel-mediated feedback system. To test the pH hypothesis in a manner independent of artificial pH-buffer systems, we studied the effect of interfering with the endogenous pH buffer, the bicarbonate/carbonic anhydrase system. Inhibition of carbonic anhydrase allowed for large changes in pH in the synaptic cleft of bipolar cell terminals and cone terminals, but the predicted enhancement of the cone feedback responses, according to the pH-hypothesis, was not observed. These experiments thus failed to support a proton mediated feedback mechanism. The alternative hypothesis, the hemichannel-mediated ephaptic feedback mechanism, was therefore studied experimentally, and its feasibility was buttressed by means of a quantitative computer model of the cone/horizontal cell synapse., Conclusion: We conclude that the data presented in this paper offers further support for physiologically relevant ephaptic interactions in the retina.

Gabapentin is a widely used drug with anticonvulsant, antinociceptive and anxiolytic properties. Although it has been previously shown that Gabapentin binds with high affinity to the alpha(2)delta subunit of voltage-operated Ca(2+) channels (VOCC), little is known about the functional consequences of this interaction. Here, we investigated the effect of Gabapentin on VOCCs and synaptic transmission in rat hippocampus and neocortex using whole-cell patch clamp and confocal imaging techniques. Gabapentin (100-300 microM) did not affect the peak amplitude or voltage-dependency of VOCC currents recorded from either dissociated or in situ neocortical and hippocampal pyramidal cells. In contrast, Gabapentin inhibited K(+)-evoked increases in [Ca(2+)] in a subset of synaptosomes isolated from rat hippocampus and neocortex in a dose-dependent manner, with an apparent half-maximal inhibitory effect at approximately 100 nM. In hippocampal slices, Gabapentin (300 microM) inhibited the amplitude of evoked excitatory- and inhibitory postsynaptic currents recorded from CA1 pyramidal cells by 30-40%. Taken together, the results suggest that Gabapentin selectively inhibits Ca(2+) influx by inhibiting VOCCs in a subset of excitatory and inhibitory presynaptic terminals, thereby attenuating synaptic transmission.