Fast inhibitory neurotransmission in mammalian nervous system is largely mediated by GABAA receptors, chloride-selective members of the superfamily of pentameric Cys-loop receptors. Native GABAA receptors are heteromeric assemblies sensitive to many important drugs, from sedatives to anesthetics and anticonvulsant agents, with mutant forms of GABAA receptors implicated in multiple neurological diseases. Despite profound importance of heteromeric GABAA receptors in neuroscience and medicine, they have proven recalcitrant to structure determination. Here we present the structure of tri-heteromeric α1β1γ2SEM GABAA receptor in complex with GABA, determined by single particle cryo-EM at 3.1-3.8 Å resolution, elucidating molecular principles of receptor assembly and agonist binding. Remarkable N-linked glycosylation on the α1 subunit occludes the extracellular vestibule of the ion channel and is poised to modulate receptor assembly and perhaps ion channel gating. Our work provides a pathway to structural studies of heteromeric GABAA receptors and a framework for rational design of novel therapeutic agents.
- Eric Gouaux
- Eric Gouaux
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Kenton Jon Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States
© 2018, Phulera 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.
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)
Previous studies have explored neurofeedback training for Parkinsonian patients to suppress beta oscillations in the subthalamic nucleus (STN). However, its impacts on movements and Parkinsonian tremor are unclear. We developed a neurofeedback paradigm targeting STN beta bursts and investigated whether neurofeedback training could improve motor initiation in Parkinson’s disease compared to passive observation. Our task additionally allowed us to test which endogenous changes in oscillatory STN activities are associated with trial-to-trial motor performance. Neurofeedback training reduced beta synchrony and increased gamma activity within the STN, and reduced beta band coupling between the STN and motor cortex. These changes were accompanied by reduced reaction times in subsequently cued movements. However, in Parkinsonian patients with pre-existing symptoms of tremor, successful volitional beta suppression was associated with an amplification of tremor which correlated with theta band activity in STN local field potentials, suggesting an additional cross-frequency interaction between STN beta and theta activities.
Microdeletions and microduplications of the 16p11.2 chromosomal locus are associated with syndromic neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations into these phenotypes, 65 clones of human induced pluripotent stem cells (hiPSCs) were generated from 13 individuals with 16p11.2 copy number variations (CNVs). To ensure these cell lines were suitable for downstream mechanistic investigations, a customizable bioinformatic strategy for the detection of random integration and expression of reprogramming vectors was developed and leveraged towards identifying a subset of ‘footprint’-free hiPSC clones. Transcriptomic profiling of cortical neural progenitor cells derived from these hiPSCs identified alterations in gene expression patterns which precede morphological abnormalities reported at later neurodevelopmental stages. Interpreting clinical information—available with the cell lines by request from the Simons Foundation Autism Research Initiative—with this transcriptional data revealed disruptions in gene programs related to both nervous system function and cellular metabolism. As demonstrated by these analyses, this publicly available resource has the potential to serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.