Expression of transcripts encoding AMPA receptor subunits and associated postsynaptic proteins in the macaque brain

Glutamate is the primary excitatory neurotransmitter in the central nervous system, regulating numerous cellular signaling pathways and controlling the excitability of central synapses both pre- and postsynaptically. Localization, cell surface expression, and activity-dependent regulation of glutamate receptors in both neurons and glia are performed and maintained by a complex network of protein–protein interactions associated with targeting, anchoring, and spatially organizing synaptic proteins at the cell membrane. Using in situ hybridization, we examined the expression of transcripts encoding the AMPA receptor subunits (GluR1–GluR4) and a family of AMPA-related intracellular proteins. We focused on PDZ-proteins that are involved in the regulated pool and anchoring AMPA subunits to the cell membrane (PICK1, syntenin), and those maintaining the constitutive pool of AMPA receptors at the glutamatergic synapse (NSF, stargazin). In addition, we studied a fifth protein, KIAA1719, with high homology to the rat PDZ protein ABP, associated with the clustering of AMPA receptors at the glutamate synapse. The AMPA subunits showed significant differences in regional expression, especially in the neocortex, thalamus, striatum, and cerebellum. The expression of other proteins, even those related to a specific AMPA subunit (such as ABP and PICK1 to GluR2 and GluR3), often had different distributions, whereas others (like NSF) are ubiquitously distributed in the brain. These results suggest that AMPA subunits and related intracellular proteins are differentially distributed in the macaque brain, and in numerous structures there are significant mismatches, suggesting additional functional properties of the associated intracellular proteins. J. Comp. Neurol. 468:530–554, 2004. © 2003 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34470/1/10981_ftp.pd

The neurodevelopmental hypothesis of schizophrenia: Convergent clues from epidemiology and neuropathology

The neurodevelopmental hypothesis of schizophrenia suggests that the disruption of early brain development increases the risk of later developing schizophrenia. This hypothesis focuses attention on critical periods of early brain development. From an epidemiologic perspective, various prenatal and perinatal risk factors have been linked to schizophrenia, including exposures related to infection, nutrition, and obstetric complications. From a genetic perspective, candidate genes have also been linked to altered brain development. In recent decades evidence from neuropathology has provided support for the neurodevelopmental hypothesis. Animal models involving early life exposures have been linked to changes in these same brain systems, providing convergent evidence for this long-standing hypothesis

The Role of Parvalbumin-positive Interneurons in Auditory Steady-State Response Deficits in Schizophrenia

© The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Despite an increasing body of evidence demonstrating subcellular alterations in parvalbumin-positive (PV+) interneurons in schizophrenia, their functional consequences remain elusive. Since PV+ interneurons are involved in the generation of fast cortical rhythms, these changes have been hypothesized to contribute to well-established alterations of beta and gamma range oscillations in patients suffering from schizophrenia. However, the precise role of these alterations and the role of different subtypes of PV+ interneurons is still unclear. Here we used a computational model of auditory steady-state response (ASSR) deficits in schizophrenia. We investigated the differential effects of decelerated synaptic dynamics, caused by subcellular alterations at two subtypes of PV+ interneurons: basket cells and chandelier cells. Our simulations suggest that subcellular alterations at basket cell synapses rather than chandelier cell synapses are the main contributor to these deficits. Particularly, basket cells might serve as target for innovative therapeutic interventions aiming at reversing the oscillatory deficits.Peer reviewe

Death and the Societies of Late Antiquity

Ce volume bilingue, comprenant un ensemble de 28 contributions disponibles en français et en anglais (dans leur version longue ou abrégée), propose d’établir un état des lieux des réflexions, recherches et études conduites sur le fait funéraire à l’époque tardo-antique au sein des provinces de l’Empire romain et sur leurs régions limitrophes, afin d’ouvrir de nouvelles perspectives sur ses évolutions possibles. Au cours des trois dernières décennies, les transformations considérables des méthodologies déployées sur le terrain et en laboratoire ont permis un renouveau des questionnements sur les populations et les pratiques funéraires de l’Antiquité tardive, période marquée par de multiples changements politiques, sociaux, démographiques et culturels. L’apparition de ce qui a été initialement désigné comme une « Anthropologie de terrain », qui fut le début de la démarche archéothanatologique, puis le récent développement d’approches collaboratives entre des domaines scientifiques divers (archéothanatologie, biochimie et géochimie, génétique, histoire, épigraphie par exemple) ont été décisives pour le renouvellement des problématiques d’étude : révision d’anciens concepts comme apparition d’axes d’analyse inédits. Les recherches rassemblées dans cet ouvrage sont articulées autour de quatre grands thèmes : l’évolution des pratiques funéraires dans le temps, l’identité sociale dans la mort, les ensembles funéraires en transformation (organisation et topographie) et les territoires de l’empire (du cœur aux marges). Ces études proposent un réexamen et une révision des données, tant anthropologiques qu’archéologiques ou historiques sur l’Antiquité tardive, et révèlent, à cet égard, une mosaïque de paysages politiques, sociaux et culturels singulièrement riches et complexes. Elles accroissent nos connaissances sur le traitement des défunts, l’emplacement des aires funéraires ou encore la structure des sépultures, en révélant une diversité de pratiques, et permettent au final de relancer la réflexion sur la manière dont les sociétés tardo-antiques envisagent la mort et sur les éléments permettant d’identifier et de définir la diversité des groupes qui les composent. Elles démontrent ce faisant que nous pouvons véritablement appréhender les structures culturelles et sociales des communautés anciennes et leurs potentielles transformations, à partir de l’étude des pratiques funéraires.This bilingual volume proposes to draw up an assessment of the recent research conducted on funerary behavior during Late Antiquity in the provinces of the Roman Empire and on their borders, in order to open new perspectives on its possible developments. The considerable transformations of the methodologies have raised the need for a renewal of the questions on the funerary practices during Late Antiquity, a period marked by multiple political, social, demographic and cultural changes. The emergence field anthropology, which was the beginning of archaeothanatology, and then the recent development of collaborative approaches between various scientific fields (archaeothanatology, biochemistry and geochemistry, genetics, history, epigraphy, for example), have been decisive. The research collected in this book is structured around four main themes: Evolution of funerary practices over time; Social identity through death; Changing burial grounds (organisation and topography); Territories of the Empire (from the heart to the margins). These studies propose a review and a revision of the data, both anthropological and archaeological or historical on Late Antiquity, and reveal a mosaic of political, social, and cultural landscapes singularly rich and complex. In doing so, they demonstrate that we can truly understand the cultural and social structures of ancient communities and their potential transformations, based on the study of funerary practices

AMPA- and NMDA-Associated Postsynaptic Protein Expression in the Human Dorsolateral Prefrontal Cortex

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74499/1/annals.1300.024.pd

Specific staining of nonpyramidal cell populations of the cerebral cortex by lectin cytochemistry on semithin sections

The pattern of lectin labeling in the cerebral cortex of the cat was studied using semithin sections. The labeling produced by some lectins (Concanavalin A, Lens culinaris, Phaseolus vulgaris-L, Phaseolus vulgaris-E, Pisum sativum, wheat germ agglutinin, and succynilated-wheat germ) appeared inside every neuron as small cytoplasmic granules, probably corresponding to cisterns of endoplasmic reticulum and/or the Golgi complex. Lectins with affinity for alpha-mannosyl residues (Pisum sativum, Lens culinaris, and Concanavalin A) stained the cell surface of a subset of cortical neurons. The labeled cells were round or polygonal, medium to large neurons present in layers II-VI, exhibiting the morphological features of nonpyramidal cells. Previous lectin studies of perineuronal nets have shown that these extracellular specializations contain N-acetylgalactosamine and N-acetylglucosamine. Our results show that mannose is also a component of perineuronal nets and that lectins specific for alpha-mannose can be used as tools for the cytochemical detection of a separate class of cortical neurons, which have not yet been fully characterized. In addition, some lectins (Bandeiraea simplicifolia, Concanavalin A, Lens culinaris, Phaseolus vulgaris-L, Phaseolus vulgaris-E, Pisum sativum, and succynilated-wheat germ agglutinin) specifically labeled a population of a type of microglia-related cells known as perivascular cells. The data presented here report for the first time the selective staining of perivascular cells and further support the hypothesis that they are different from typical microglial cells.This work was supported by grants of the Spanish Government (DGICYT PB93-0928 and PM96-0082) and a personal fellowship to Mónica Beneyto (Generalitat Valenciana 199600564).Peer reviewe

Molecular Abnormalities of the Glutamate Synapse in the Thalamus in Schizophrenia

Schizophrenia has been associated with dysfunction of glutamatergic neurotransmission. Synaptic glutamate activates pre- and postsynaptic ionotropic NMDA, AMPA, and kainate and metabotropic receptors, is removed from the synapse via five cell surface-expressed transporters, and is packaged for release by three vesicular transporters. In addition, there is a family of intracellular molecules enriched in the postsynaptic density (PSD) that target glutamate receptors to the synaptic membrane, modulate receptor activity, and coordinate glutamate receptor-related signal transduction. Each family of PSD proteins is selective for a given glutamate receptor subtype, the most well characterized being the NMDA receptor binding proteins PSD93, PSD95, NF-L, and SAP102. Besides binding glutamate receptors, many of these proteins also interact with cell surface proteins like cell adhesion molecules, ion channels, cytoskeletal elements, and signal transduction molecules. Given the complexity of the glutamate neurotransmitter system, there are many locations where disruption of normal signaling could occur and give rise to abnormal glutamatergic neurotransmission in schizophrenia. Using multiple cohorts of postmortem tissue, we have examined these synaptic molecules in schizophrenic thalamus. The expression of NR1 and NR2C subunit transcripts is decreased in the thalamus in schizophrenia. Interestingly, three intracellular PSD molecules that link the NMDA receptor to signal transduction pathways are also abnormally expressed. Additionally, several of the cell surface and vesicular transporters are abnormal in the schizophrenic thalamus. While occasional findings of abnormal receptor expression are made, the most dramatic and consistent alterations that we have found in the thalamus in schizophrenia involve the family of intracellular signaling/scaffolding molecules. We propose that schizophrenia has a glutamatergic component that involves alterations in the intracellular machinery that is coupled to glutamate receptors, in addition to abnormalities of the receptors themselves. Our data suggest that schizophrenia is associated with abnormal glutamate receptor-related intracellular signaling in the thalamus, and point to novel targets for innovative drug discovery.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75484/1/annals.1300.005.pd

Lamina-Specific Alterations in Cortical GABAA Receptor Subunit Expression in Schizophrenia

Dysfunction of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia is associated with lamina-specific alterations in particular subpopulations of interneurons. In pyramidal cells, postsynaptic γ-aminobutyric acid (GABAA) receptors containing different α subunits are inserted preferentially in distinct subcellular locations targeted by inputs from specific interneuron subpopulations. We used in situ hybridization to quantify the laminar expression of α1, α2, α3, and α5 subunit, and of β1-3 subunit, mRNAs in the DLFPC of schizophrenia, and matched normal comparison subjects. In subjects with schizophrenia, mean GABAA α1 mRNA expression was 17% lower in layers 3 and 4, α2 expression was 14% higher in layer 2, α5 expression was 15% lower in layer 4, and α3 expression did not differ relative to comparison subjects. The mRNA expression of β2, which preferentially assembles with α1 subunits, was also 20% lower in layers 3 and 4, whereas β1 and β3 mRNA levels were not altered in schizophrenia. These expression differences were not attributable to medication effects or other potential confounds. These findings suggest that GABA neurotransmission in the DLPFC is altered at the postsynaptic level in a receptor subunit- and layer-specific manner in subjects with schizophrenia and support the hypothesis that GABA neurotransmission in this illness is predominantly impaired in certain cortical microcircuits