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Type A γ-aminobutyric acid (GABA A ) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system 1 , 2 . Their dysfunction is implicated in a range of neurological disorders, including depression, epilepsy and schizophrenia 3 , 4 . Among the numerous assemblies that are theoretically possible, the most prevalent in the brain are the α1β2/3γ2 GABA A receptors 5 . The β3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in β1–β3 triple knockout neurons 6 . So far, efforts to generate accurate structural models for heteromeric GABA A receptors have been hampered by the use of engineered receptors and the presence of detergents 7 – 9 . Notably, some recent cryo-electron microscopy reconstructions have reported ‘collapsed’ conformations 8 , 9 ; however, these disagree with the structure of the prototypical pentameric ligand-gated ion channel the Torpedo nicotinic acetylcholine receptor 10 , 11 , the large body of structural work on homologous homopentameric receptor variants 12 and the logic of an ion-channel architecture. Here we present a high-resolution cryo-electron microscopy structure of the full-length human α1β3γ2L—a major synaptic GABA A receptor isoform—that is functionally reconstituted in lipid nanodiscs. The receptor is bound to a positive allosteric modulator ‘megabody’ and is in a desensitized conformation. Each GABA A receptor pentamer contains two phosphatidylinositol-4,5-bisphosphate molecules, the head groups of which occupy positively charged pockets in the intracellular juxtamembrane regions of α1 subunits. Beyond this level, the intracellular M3–M4 loops are largely disordered, possibly because interacting post-synaptic proteins are not present. This structure illustrates the molecular principles of heteromeric GABA A receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology. A high-resolution cryo-electron microscopy structure is reported for the full-length human α1β3γ2L GABA A receptor, functionally reconstituted in lipid nanodiscs.

Editorial do Golpe de 1964

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.Hansen et al. compile and share an atlas of neurotransmitter receptor/transporter densities in the human cortex and show that receptor achitecture reflects brain structure, function, dynamics, cognitive specialization and disease vulnerability.

Neurotransmitters and neuromodulators have a wide range of key roles throughout the nervous system. However, their dynamics in both health and disease have been challenging to assess, owing to the lack of in vivo tools to track them with high spatiotemporal resolution. Thus, developing a platform that enables minimally invasive, large-scale and long-term monitoring of neurotransmitters and neuromodulators with high sensitivity, high molecular specificity and high spatiotemporal resolution has been essential. Here, we review the methods available for monitoring the dynamics of neurotransmitters and neuromodulators. Following a brief summary of non-genetically encoded methods, we focus on recent developments in genetically encoded fluorescent indicators, highlighting how these novel indicators have facilitated advances in our understanding of the functional roles of neurotransmitters and neuromodulators in the nervous system. These studies present a promising outlook for the future development and use of tools to monitor neurotransmitters and neuromodulators.The levels of neurotransmitters and neuromodulators have been difficult to track. In this Review, Wu et al. give an overview of conventional and modern tools and imaging methods for monitoring neurochemicals, with a focus on genetically encoded sensors.

What happens to marginalized groups from Africa when they ally with the indigenous peoples' movement? Who claims to be indigenous and why? Dorothy L. Hodgson explores how indigenous identity, both in concept and in practice, plays out in the context of economic liberalization, transnational capitalism, state restructuring, and political democratization. Hodgson brings her long experience with Maasai to her understanding of the shifting contours of their contemporary struggles for recognition, representation, rights, and resources. Being Maasai, Becoming Indigenous is a deep and sensitive reflection on the possibilities and limits of transnational advocacy and the dilemmas of political action, civil society, and change in Maasai communities.

Key Points Although also being a characteristic of normal behaviour, excessive impulsivity is an important symptom of several neuropsychiatric and neurological disorders, including addiction, attention-deficit hyperactivity disorder and Parkinson disease. However, impulsivity may comprise several apparently related forms that depend on distinct neuropsychological processes and neural systems. Of particular importance are interactions between frontostriatal systems and their neurochemical modulation, which are also providing new insights into the functions of these systems in behaviour. The psychological and neural basis of impulsivity can be studied in a mutually profitable way in experimental animals and in humans. Striking parallels can be observed in the underlying neurobehavioural systems, allowing both macro- and micro-definition of functional circuits. The dissection of impulsivity in this Review may represent a way in which complex behaviour relevant to psychiatric disorders can be broken down into its constituent parts, thus allowing for improved genetic understanding and more-precise treatments at the level of symptoms rather than according to categorical diagnoses of mental health disorders. Impulsivity comes in various forms, with some forms considered more or less advantageous than others. Dalley and Robbins review the different types of impulsivity and their underlying neural mechanisms, and comment on the applicability of measures of impulsivity in research into psychiatric disorders. The ability to make decisions and act quickly without hesitation can be advantageous in many settings. However, when persistently expressed, impulsive decisions and actions are considered risky, maladaptive and symptomatic of such diverse brain disorders as attention-deficit hyperactivity disorder, drug addiction and affective disorders. Over the past decade, rapid progress has been made in the identification of discrete neural networks that underlie different forms of impulsivity — from impaired response inhibition and risky decision making to a profound intolerance of delayed rewards. Herein, we review what is currently known about the neural and psychological mechanisms of impulsivity, and discuss the relevance and application of these new insights to various neuropsychiatric disorders.