RIM-Binding Protein 2 organizes Ca2+ channel topography and regulates release probability and vesicle replenishment at a fast central synapse

RIM-Binding Protein 2 (RIM-BP2) is a multi-domain protein of the presynaptic active zone (AZ). By binding to Rab-interacting protein (RIM), bassoon and voltage-gated Ca2+ channels (CaV), it is considered to be a central organizer of the topography of CaV and release sites of synaptic vesicles (SVs) at the AZ. Here, we investigated the role of RIM-BP2 at the endbulb of Held synapse of auditory nerve fibers with bushy cells of the cochlear nucleus, a fast relay of the auditory pathway with high release probability. Disruption of RIM-BP2 lowered release probability altering short-term plasticity and reduced evoked excitatory postsynaptic currents (EPSCs). Analysis of SV pool dynamics during high frequency train stimulation indicated a reduction of SVs with high release probability but an overall normal size of the readily releasable SV pool (RRP). The Ca2+-dependent fast component of SV replenishment after RRP depletion was slowed. Augmenting Ca2+ influx by adding extracellular Ca2+ restored release probability but not EPSC amplitude, and uncovered an impairment of SV replenishment during train stimulation. Ultrastructural analysis by super-resolution light and electron microscopy revealed an impaired topography of presynaptic CaV and a reduction of docked and membrane-proximal SVs at the AZ. We conclude that RIM-BP2 organizes the topography of CaV, and promotes SV tethering and docking. This way RIM-BP2 is critical for establishing a high initial release probability as required to reliably signal sound onset information that we found to be degraded in bushy cells of RIM-BP2-deficient mice in vivo.

Imperceptible Somatosensory Single Pulse and Pulse Train Stimulation Oppositely Modulate Mu Rhythm Activity and Perceptual Performance

Subliminal stimulation alters conscious perception – a potential mechanism is the modulation of cortical background rhythms especially in the alpha range. Here, in the human somatosensory domain, we assessed effects of subthreshold (imperceptible) electrical finger nerve stimulation – either presented as single pulses or as brief (1 s) 7 Hz pulse trains—on mu-alpha rhythm and perceptual performance. In electroencephalography, subthreshold single pulses transiently (~150–350 ms poststimulus) increased mu activity (event-related synchronization), while, interestingly, subthreshold trains led to prolonged (>1 s) mu desynchronization. In psychophysics, detection of near-threshold target stimuli was consistently reduced when presented together with subthreshold trains (at three delays), whereas for targets paired with subthreshold single pulses detection remained unaffected (30 and 180 ms) or was even elevated (60 ms). Though both imperceptible, single pulses and pulse trains exerted opposite effects on neural signaling and perception. We suggest that the common neural basis is preferential activation of cortical inhibitory interneurons. While the inhibitory impact of a subthreshold single pulse (reflected by mu synchronization) is not psychophysically detectable—rather perception may be facilitated—repetition of the same subthreshold pulse shifts the excitation-inhibition balance toward an inhibitory cortical state (reflected by perceptual impediment) accompanied by mu desynchronization. These differential findings provide novel insights on the notion of alpha activity mediating functional inhibition.

Water intake after dehydration makes muscles more susceptible to cramp but electrolytes reverse that effect

ObjectiveNo previous study has compared water and oral rehydration solution (ORS) intake after dehydration induced by exercise in the heat for the effect on muscle cramps. The present study tested the hypothesis that water ingestion after dehydration would increase muscle cramp susceptibility, but this would be prevented by ORS ingestion.MethodsTen men performed two bouts of downhill running (DHR; −5%) in the heat (35°C–36 °C) until their body mass was reduced by 2%. Ten minutes after DHR, either spring water or electrolyte water similar to ORS (OS-1®) was ingested in a counter-balanced order on two different days separated by a week. Muscle cramp susceptibility was assessed by a threshold frequency (TF) of electrical train stimulation to induce cramp before, immediately after (0), and 30 and 60 min after the ingestion. Blood samples were taken before, immediately and 80 min after DHR to measure serum electrolyte concentrations.ResultsMuscle cramp susceptibility assessed by TF did not change from baseline to immediately after DHR for both conditions (water: 24.6 ± 2.1 Hz, OS-1®: 24.7 ± 1.4 Hz). TF decreased after water intake by 4.3 Hz (30 min) and 5.1 Hz (60 min post-ingestion), but increased after OS-1®intake by 3.7 and 5.4 Hz, respectively. Serum sodium and chloride concentrations decreased after water intake but maintained after OS-1®intake.ConclusionThese results suggest that water intake after dehydration makes muscles more susceptible to electrical simulation-induced muscle cramp, probably due to dilution of electrolytes, and when OS-1®is consumed, the susceptibility to muscle cramp decreases.

Intraoperative identification of the corticospinal tract and dorsal column of the spinal cord by electrical stimulation

ObjectivesAnatomical identification of the corticospinal tract (CT) and the dorsal column (DC) of the exposed spinal cord is difficult when anatomical landmarks are distorted by tumour growth. Neurophysiological identification is complicated by the fact that direct stimulation of the DC may result in muscle motor responses due to the centrally activated H-reflex. This study aims to provide a technique for intraoperative neurophysiological differentiation between CT and DC in the exposed spinal cord.MethodsRecordings were obtained from 32 consecutive patients undergoing spinal cord tumour surgery from July 2015 to March 2017. A double train stimulation paradigm with an intertrain interval of 60 ms was devised with recording of responses from limb muscles.ResultsIn non-spastic patients (55% of cohort) an identical second response was noted following the first CT response, but the second response was absent after DC stimulation. In patients with pre-existing spasticity (45%), CT stimulation again resulted in two identical responses, whereas DC stimulation generated a second response that differed substantially from the first one. The recovery times of interneurons in the spinal cord grey matter were much shorter for the CT than those for the DC. Therefore, when a second stimulus train was applied 60 ms after the first, the CT-fibre interneurons had already recovered ready to generate a second response, whereas the DC interneurons were still in the refractory period.ConclusionsMapping of the spinal cord using double train stimulation allows neurophysiological distinction of CT from DC pathways during spinal cord surgery in patients with and without pre-existing spasticity.