Asymmetric Excitatory Synaptic Dynamics Underlie Interaural Time Difference Processing in the Auditory System

In order to localize sounds in the environment, the auditory system detects and encodes differences in signals between each ear. The exquisite sensitivity of auditory brain stem neurons to the differences in rise time of the excitation signals from the two ears allows for neuronal encoding of microsecond interaural time differences

Visual Stimuli Evoked Action Potentials Trigger Rapidly Propagating Dendritic Calcium Transients in the Frog Optic Tectum Layer 6 Neurons.

The superior colliculus in mammals or the optic tectum in amphibians is a major visual information processing center responsible for generation of orientating responses such as saccades in monkeys or prey catching avoidance behavior in frogs. The conserved structure function of the superior colliculus the optic tectum across distant species such as frogs, birds monkeys permits to draw rather general conclusions after studying a single species. We chose the frog optic tectum because we are able to perform whole-cell voltage-clamp recordings fluorescence imaging of tectal neurons while they respond to a visual stimulus. In the optic tectum of amphibians most visual information is processed by pear-shaped neurons possessing long dendritic branches, which receive the majority of synapses originating from the retinal ganglion cells. Since the first step of the retinal input integration is performed on these dendrites, it is important to know whether this integration is enhanced by active dendritic properties. We demonstrate that rapid calcium transients coinciding with the visual stimulus evoked action potentials in the somatic recordings can be readily detected up to the fine branches of these dendrites. These transients were blocked by calcium channel blockers nifedipine CdCl2 indicating that calcium entered dendrites via voltage-activated L-type calcium channels. The high speed of calcium transient propagation, >300 μm in <10 ms, is consistent with the notion that action potentials, actively propagating along dendrites, open voltage-gated L-type calcium channels causing rapid calcium concentration transients in the dendrites. We conclude that such activation by somatic action potentials of the dendritic voltage gated calcium channels in the close vicinity to the synapses formed by axons of the retinal ganglion cells may facilitate visual information processing in the principal neurons of the frog optic tectum

Action potentials actively propagating along dendrites are responsible for calcium concentration transients detected by OGB-1 dye.

<p><b><i>A</i></b>. All detected Ca_i²⁺ increases coincided with action potentials. In this trace three action potentials correspond to three steps of OGB-1 signal increases. <b><i>B</i></b>. During current injection all 7 action potentials caused OGB-1 fluorescence intensity increases. <b><i>C</i></b>. The first action potential from B is shown on faster time scale with a corresponding OGB-1 fluorescence signal. It is clear that all increase in OGB-1 fluorescence occurred within few milliseconds of the action potential occurrence. The fluorescence sampling rate was 440 Hz. The vertical bar serves as a scale for both the voltage (20 mV) relative fluorescence change, dF/F, 5%. <b><i>D E</i></b>. Calcium influx was similar during action potentials evoked by a voltage step a visual stimulus. In <b><i>D</i></b> current traces evoked by a visual stimulus (a ~20° wide black circle in the center of the receptive field) during voltage steps (a 40 mV, 20 ms long voltage step, bottom black traces) are shown in slow in fast time scales (left right panels correspondingly). Leak currents capacitance charging transients were subtracted for clarity. In <b><i>E</i></b> fluorescence traces for both conditions are aligned at the onset of the responses. Grey filled circles correspond to visually evoked stimulus while black filled circles correspond to voltage step comm. In addition, a fluorescence trace corresponding to OFF visual stimulus is shown as a dark grey line. Although no membrane currents are shown for this stimulation, two action potentials were also evoked during this OFF stimulus albeit with larger interval that explains slightly slower rate of rise of the fluorescence signal. For all three conditions the fluorescence measurements were taken in the same dendrite section at about 100 μm from the soma. <b><i>F G</i></b>. OGB-1 fluorescence increase could be detected up to >300 μm from the soma in the area of fine dendritic branches near the edge of the optic tectum. In all three locations the onset of the OGB-1 signal increase was nearly simultaneous, probably limited by the fluorescence signal sampling rate of 100 Hz. A vertical thick grey broken line in <b><i>G</i></b> denotes the onset of the inward synaptic currents while the horizontal thin black broken line denotes the 0 pA baseline for the current trace.</p

Effects of Metformin on Spontaneous Ca2+ Signals in Cultured Microglia Cells under Normoxic and Hypoxic Conditions

Microglial functioning depends on Ca2+ signaling. By using Ca2+ sensitive fluorescence dye, we studied how inhibition of mitochondrial respiration changed spontaneous Ca2+ signals in soma of microglial cells from 5–7-day-old rats grown under normoxic and mild-hypoxic conditions. In microglia under normoxic conditions, metformin or rotenone elevated the rate and the amplitude of Ca2+ signals 10–15 min after drug application. Addition of cyclosporin A, a blocker of mitochondrial permeability transition pore (mPTP), antioxidant trolox, or inositol 1,4,5-trisphosphate receptor (IP3R) blocker caffeine in the presence of rotenone reduced the elevated rate and the amplitude of the signals implying sensitivity to reactive oxygen species (ROS), and involvement of mitochondrial mPTP together with IP3R. Microglial cells exposed to mild hypoxic conditions for 24 h showed elevated rate and increased amplitude of Ca2+ signals. Application of metformin or rotenone but not phenformin before mild hypoxia reduced this elevated rate. Thus, metformin and rotenone had the opposing fast action in normoxia after 10–15 min and the slow action during 24 h mild-hypoxia implying activation of different signaling pathways. The slow action of metformin through inhibition of complex I could stabilize Ca2+ homeostasis after mild hypoxia and could be important for reduction of ischemia-induced microglial activation