Voltage-gated ion channels support electrochemical activity in cells and are largely responsible for information flow throughout the nervous systems. The voltage sensor domains in these channels sense changes in transmembrane potential and control ion flux across membranes. The X-ray structures of a few voltage-gated ion channels in detergents have been determined and have revealed clear structural variations among their respective voltage sensor domains. More recent studies demonstrated that lipids around a voltage-gated channel could directly alter its conformational state in membrane. Because of these disparities, the structural basis for voltage sensing in native membranes remains elusive. Here, through electron-crystallographic analysis of membrane-embedded proteins, we present the detailed view of a voltage-gated potassium channel in its inactivated state. Contrary to all known structures of voltage-gated ion channels in detergents, our data revealed a unique conformation in which the four voltage sensor domains of a voltage-gated potassium channel from Aeropyrum pernix (KvAP) form a ring structure that completely surrounds the pore domain of the channel. Such a structure is named the voltage sensor ring. Our biochemical and electrophysiological studies support that the voltage sensor ring represents a physiological conformation. These data together suggest that lipids exert strong effects on the channel structure and that these effects may be changed upon membrane disruption. Our results have wide implications for lipid-protein interactions in general and for the mechanism of voltage sensing in particular.

In rats, navigating through an environment requires continuous information about objects near the head. Sensory information such as object location and surface texture are encoded by spike firing patterns of single neurons within rat barrel cortex. Although there are many studies using single-unit electrophysiology, much less is known regarding the spatiotemporal pattern of activity of populations of neurons in barrel cortex in response to whisker stimulation. To examine cortical response at the population level, we used voltage-sensitive dye (VSD) imaging to examine ensemble spatiotemporal dynamics of barrel cortex in response to stimulation of single or two adjacent whiskers in urethane-anesthetized rats. Single whisker stimulation produced a poststimulus fluorescence response peak within 12-16 ms in the barrel corresponding to the stimulated whisker (principal whisker). This fluorescence subsequently propagated throughout the barrel field, spreading anisotropically preferentially along a barrel row. After paired whisker stimulation, the VSD signal showed sublinear summation (less than the sum of 2 single whisker stimulations), consistent with previous electrophysiological and imaging studies. Surprisingly, we observed a spatial shift in the center of activation occurring over a 10- to 20-ms period with shift magnitudes of 1-2 barrels. This shift occurred predominantly in the posteromedial direction within the barrel field. Our data thus reveal previously unreported spatiotemporal patterns of barrel cortex activation. We suggest that this nontopographical shift is consistent with known functional and anatomic asymmetries in barrel cortex and that it may provide an important insight for understanding barrel field activation during whisking behavior.

Brain function relies on communication between large populations of neurons across multiple brain areas, a full understanding of which would require knowledge of the time-varying activity of all neurons in the central nervous system. Here we use light-sheet microscopy to record activity, reported through the genetically encoded calcium indicator GCaMP5G, from the entire volume of the brain of the larval zebrafish in vivo at 0.8 Hz, capturing more than 80% of all neurons at single-cell resolution. Demonstrating how this technique can be used to reveal functionally defined circuits across the brain, we identify two populations of neurons with correlated activity patterns. One circuit consists of hindbrain neurons functionally coupled to spinal cord neuropil. The other consists of an anatomically symmetric population in the anterior hindbrain, with activity in the left and right halves oscillating in antiphase, on a timescale of 20 s, and coupled to equally slow oscillations in the inferior olive.

Objective: While the contribution of α-Synuclein to neurodegeneration in Parkinson’s disease is well accepted, the putative impact of its close homologue, β-Synuclein, is enigmatic. β-Synuclein is widely expressed throughout the central nervous system as is α-Synuclein, but the physiological functions of both proteins remain unknown. Recent findings supported the view that β-Synuclein can act as an ameliorating regulator of α-Synuclein-induced neurotoxicity, having neuroprotective rather than neurodegenerative capabilities, and being non-aggregating due to absence of most part of the aggregation-promoting NAC domain. However, a mutation of β-Synuclein linked to dementia with Lewy bodies rendered the protein neurotoxic in transgenic mice and fibrillation of β-Synuclein has been demonstrated in vitro. Methods / Results: Supporting the hypothesis that β-Synuclein can act as a neurodegeneration-inducing factor we now demonstrate that wild-type β-Synuclein is neurotoxic for cultured primary neurons. Furthermore, β-Synuclein formed proteinase K resistant aggregates in dopaminergic neurons in vivo, leading to pronounced and progressive neurodegeneration in rats. Expression of β-Synuclein caused mitochondrial fragmentation, but this fragmentation did not render mitochondria non-functional in terms of ion handling and respiration even in late stages of neurodegeneration. A comparison of the neurodegenerative effects induced by α-, β-, and γ-Synuclein revealed that β-Synuclein was eventually as neurotoxic as α-Synuclein for nigral dopaminergic neurons, while γ-Synuclein proved to be non-toxic and had very low aggregation propensity. Interpretation: Our results suggest that the role of β-Synuclein as a putative modulator of neuropathology in aggregopathies like Parkinson’s disease and dementia with Lewy bodies needs to be revisited. ANN NEUROL 2013. © 2013 American Neurological Association.