Culture, Neurobiology, and Human Behavior: New Perspectives in Anthropology

Our primary goal in this article is to discuss the cross-talk between biological and cultural factors that become manifested in the individual brain development, neural wiring, neurochemical homeostasis, and behavior. We will show that behavioral propensities are the product of both cultural and biological factors and an understanding of these interactive processes can provide deep insights into why people behave the way they do. This interdisciplinary perspective is offered in an effort to generate dialog and empirical work among scholars interested in merging aspects of anthropology and neuroscience, and anticipates that biological and cultural anthropology converge. We discuss new theoretical developments, hypothesis-testing strategies, and cross-disciplinary methods of observation and data collection. We believe that the exigency of integrating anthropology and the neurosciences is indisputable and anthropology's role in an emerging interdisciplinary science of human behavior will be critical because its focus is, and has always been, on human biological and cultural systems

Identification of amino acid residues important for assembly of GABA receptor alpha1 and gamma2 subunits

Abstract Comparative models of GABA A receptors composed of a1b3c2 subunits were generated using the acetylcholinebinding protein (AChBP) as a template and were used for predicting putative engineered cross-link sites between the a1 and the c2 subunit. The respective amino acid residues were substituted by cysteines and disulfide bond formation between subunits was investigated on co-transfection into human embryonic kidney (HEK) cells. Although disulfide bond formation between subunits could not be observed, results indicated that mutations studied influenced assembly of GABA A receptors. Whereas residue a1A108 was important for the formation of assembly intermediates with b3 and c2 subunits consistent with its proposed location at the a1(+) side of GABA A receptors, residues c2T125 and c2P127 were important for assembly with b3 subunits. Mutation of each of these residues also caused an impaired expression of receptors at the cell surface. In contrast, mutated residues a1F99C, a1S106C or c2T126C only impaired the formation of receptors at the cell surface when co-expressed with subunits in which their predicted interaction partner was also mutated. These data are consistent with the prediction that the mutated residue pairs are located close to each other

Structure of excitatory synapses and GABA

Formation, maintenance, and activity of excitatory and inhibitory synapses are essential for neuronal network function. Cell adhesion molecules (CAMs) are crucially involved in these processes. The CAM neuroplastin-65 (Np65) highly expressed during periods of synapse formation and stabilization is present at the pre- and postsynaptic membranes. Np65 can translocate into synapses in response to electrical stimulation and it interacts with subtypes of GABA <inf>A</inf> receptors in inhibitory synapses. Here, we report that in the murine hippocampus and in hippocampal primary culture, neurons of the CA1 region and the dentate gyrus (DG) express high Np65 levels, whereas expression in CA3 neurons is lower. In neuroplastin-deficient (Np<sup>-/-</sup>) mice the number of excitatory synapses in CA1 and DG, but not CA3 regions is reduced. Notably this picture is mirrored in mature Np<sup>-/-</sup> hippocampal cultures or in mature CA1 and DG wild-type (Np<sup>+/+</sup>) neurons treated with

Regulation of GABAA Receptor Dynamics by Interaction with Purinergic P2X2 Receptors*

γ-Aminobutyric acid type A receptors (GABAARs) in the spinal cord are evolving as an important target for drug development against pain. Purinergic P2X2 receptors (P2X2Rs) are also expressed in spinal cord neurons and are known to cross-talk with GABAARs. Here, we investigated a possible “dynamic” interaction between GABAARs and P2X2Rs using co-immunoprecipitation and fluorescence resonance energy transfer (FRET) studies in human embryonic kidney (HEK) 293 cells along with co-localization and single particle tracking studies in spinal cord neurons. Our results suggest that a significant proportion of P2X2Rs forms a transient complex with GABAARs inside the cell, thus stabilizing these receptors and using them for co-trafficking to the cell surface, where P2X2Rs and GABAARs are primarily located extra-synaptically. Furthermore, agonist-induced activation of P2X2Rs results in a Ca2+-dependent as well as an apparently Ca2+-independent increase in the mobility and an enhanced degradation of GABAARs, whereas P2X2Rs are stabilized and form larger clusters. Antagonist-induced blocking of P2XRs results in co-stabilization of this receptor complex at the cell surface. These results suggest a novel mechanism where association of P2X2Rs and GABAARs could be used for specific targeting to neuronal membranes, thus providing an extrasynaptic receptor reserve that could regulate the excitability of neurons. We further conclude that blocking the excitatory activity of excessively released ATP under diseased state by P2XR antagonists could simultaneously enhance synaptic inhibition mediated by GABAARs

Engineered Flumazenil Recognition Site Provides Mechanistic Insight Governing Benzodiazepine Modulation in GABA_A Receptors

The anxiolytic, anticonvulsant, muscle-relaxant, and sedative-hypnotic effects of benzodiazepine site ligands are mainly elicited by allosteric modulation of GABA_A receptors via their extracellular αx+/γ2– (<i>x</i> = 1, 2, 3, 5) interfaces. In addition, a low affinity binding site at the homologous α+/β– interfaces was reported for some benzodiazepine site ligands. Classical benzodiazepines and pyrazoloquinolinones have been used as molecular probes to develop structure–activity relationship models for benzodiazepine site activity. Considering all possible α+/β– and α+/γ– interfaces, such ligands potentially interact with as many as 36 interfaces, giving rise to undesired side effects. Understanding the binding modes at their binding sites will enable rational strategies to design ligands with desired selectivity profiles. Here, we compared benzodiazepine site ligand interactions in the high affinity α1+/γ2– site with the homologous α1+/β3– site using a successive mutational approach. We incorporated key amino acids known to contribute to high affinity benzodiazepine binding of the γ2– subunit into the β3– subunit, resulting in a quadruple mutant β3­(4mut) with high affinity flumazenil (Ro 15-1788) binding properties. Intriguingly, some benzodiazepine site ligands displayed positive allosteric modulation in the tested recombinant α1β3­(4mut) constructs while diazepam remained inactive. Consequently, we performed <i>in silico</i> molecular docking in the wildtype receptor and the quadruple mutant. The results led to the conclusion that different benzodiazepine site ligands seem to use distinct binding modes, rather than a common binding mode. These findings provide structural hypotheses for the future optimization of both benzodiazepine site ligands, and ligands that interact with the homologous α+/β– sites

Diversity lost: COVID-19 as a phenomenon of the total environment

If we want to learn how to deal with the COVID-19 pandemic, we have to embrace the complexity of this global phenomenon and capture interdependencies across scales and contexts. Yet,we still lack systematic approaches that we can use to deal holistically with the pandemic and its effects. In this Discussion, we first introduce a framework that highlights the systemic nature of the COVID-19 pandemic fromthe perspective of the total environment as a self-regulating and evolving system comprising of three spheres, the Geosphere, the Biosphere, and the Anthroposphere. Then,we use this framework to explore and organize information from the rapidly growing number of scientific papers, preprints, preliminary scientific reports, and journalistic pieces that give insights into the pandemic crisis. With this work, we point out that the pandemic should be understood as the result of preconditions that led to depletion of human, biological, and geochemical diversity aswell as of feedback that differentially impacted the three spheres. We contend that protecting and promoting diversity, is necessary to contribute to more effective decision-making processes and policy interventions to face the current and future pandemics