Synapses are fundamental information processing units that rely on voltage-gated Ca2+ (Cav) channels to trigger Ca2+-dependent neurotransmitter release. Cav channels also play Ca2+-independent roles in other biological contexts, but whether they do so in axon terminals is unknown. Here, we addressed this unknown with respect to the requirement for Cav1.4 L-type channels for the formation of rod photoreceptor synapses in the retina. Using a mouse strain expressing a non-conducting mutant form of Cav1.4, we report that the Cav1.4 protein, but not its Ca2+ conductance, is required for the molecular assembly of rod synapses; however, Cav1.4 Ca2+ signals are needed for the appropriate recruitment of postsynaptic partners. Our results support a model in which presynaptic Cav channels serve both as organizers of synaptic building blocks and as sources of Ca2+ ions in building the first synapse of the visual pathway and perhaps more broadly in the nervous system.
All data generated or analysed during this study are included in the manuscript and supporting files
- Amy Lee
- Mrinalini Hoon
- Mrinalini Hoon
- J Wesley Maddox
- Brittany Williams
- Nikolai Artemyev
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#7121262-025) of the University of Iowa. The protocol was approved by the Office of Institutional Animal Care and Use Committee of the University of Iowa (A3021-01).
- Teresa Giraldez, Universidad de La Laguna, Spain
© 2020, Maddox et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Acid-sensing ion channels (ASICs) are trimeric proton-gated sodium channels. Recent work has shown that these channels play a role in necroptosis following prolonged acidic exposure like occurs in stroke. The C-terminus of ASIC1a is thought to mediate necroptotic cell death through interaction with receptor interacting serine threonine kinase 1 (RIPK1). This interaction is hypothesized to be inhibited at rest via an interaction between the C- and N-termini which blocks the RIPK1 binding site. Here, we use two transition metal ion FRET methods to investigate the conformational dynamics of the termini at neutral and acidic pH. We do not find evidence that the termini are close enough to be bound while the channel is at rest and find that the termini may modestly move closer together during acidification. At rest, the N-terminus adopts a conformation parallel to the membrane about 10 Å away. The distal end of the C-terminus may also spend time close to the membrane at rest. After acidification, the proximal portion of the N-terminus moves marginally closer to the membrane whereas the distal portion of the C-terminus swings away from the membrane. Together these data suggest that a new hypothesis for RIPK1 binding during stroke is needed.
Decisions under uncertainty are often biased by the history of preceding sensory input, behavioral choices, or received outcomes. Behavioral studies of perceptual decisions suggest that such history-dependent biases affect the accumulation of evidence and can be adapted to the correlation structure of the sensory environment. Here, we systematically varied this correlation structure while human participants performed a canonical perceptual choice task. We tracked the trial-by-trial variations of history biases via behavioral modeling and of a neural signature of decision formation via magnetoencephalography (MEG). The history bias was flexibly adapted to the environment and exerted a selective effect on the build-up (not baseline level) of action-selective motor cortical activity during decision formation. This effect added to the impact of the current stimulus. We conclude that the build-up of action plans in human motor cortical circuits is shaped by dynamic prior expectations that result from an adaptive interaction with the environment.