Signal transduction at vertebrate excitatory synapses involves the rapid activation of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptors, glutamate-gated ion channels whose four subunits assemble as a dimer-of-dimers. Technical advances in cryo-electron microscopy brought a slew of full-length structures of AMPA receptors, on their own and in combination with auxiliary subunits. These structures indicate that dimers might undergo substantial lateral motions during gating, opening up the extracellular layer along the central 2-fold symmetry axis. We used bifunctional methanethiosulfonate cross-linkers to calibrate the conformations found in functional AMPA receptors in the presence and absence of the auxiliary subunit Stargazin. Our data indicate that extracellular layer of AMPA receptors can get trapped in stable, opened-up conformations, especially upon long exposures to glutamate. In contrast, Stargazin limits this conformational flexibility. Thus, under synaptic conditions, where brief glutamate exposures and the presence of auxiliary proteins dominate, extracellular domains of AMPA receptors likely stay compact during gating.
- Andrew J R Plested
- Andrew J R Plested
- Andrew J R Plested
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- László Csanády, Semmelweis University, Hungary
© 2018, Baranovic & Plested
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.
Downloads (link to download the article as PDF)
Download citations (links to download the citations from this article in formats compatible with various reference manager tools)
Open citations (links to open the citations from this article in various online reference manager services)
The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Δ9-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo. Boosting autophagy, either pharmacologically (with temsirolimus) or by dietary intervention (with trehalose), rescued the Δ9-tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagy-modulating strategies in vivo showed that cannabinoid CB1 receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of Δ9-tetrahydrocannabinol by inhibiting local autophagy. Taken together, these findings identify inhibition of autophagy as an unprecedented mechanistic link between cannabinoids and motor performance, and suggest that activators of autophagy might be considered as potential therapeutic tools to treat specific cannabinoid-evoked behavioral alterations.
Goal-directed behaviours may be poorly coordinated in young animals but, with age and experience, behaviour progressively adapts to efficiently exploit the animal's ecological niche. How experience impinges on the developing neural circuits of behaviour is an open question. We have conducted a detailed study of the effects of experience on the ontogeny of hunting behaviour in larval zebrafish. We report that larvae with prior experience of live prey consume considerably more prey than naive larvae. This is mainly due to increased capture success and a modest increase in hunt rate. We demonstrate that the initial turn to prey and the final capture manoeuvre of the hunting sequence were jointly modified by experience and that modification of these components predicted capture success. Our findings establish an ethologically relevant paradigm in zebrafish for studying how the brain is shaped by experience to drive the ontogeny of efficient behaviour.