Epilepsy, E/I Balance and GABAA Receptor Plasticity

GABAA receptors mediate most of the fast inhibitory transmission in the CNS. They form heteromeric complexes assembled from a large family of subunit genes. The existence of multiple GABAA receptor subtypes differing in subunit composition, localization and functional properties underlies their role for fine-tuning of neuronal circuits and genesis of network oscillations. The differential regulation of GABAA receptor subtypes represents a major facet of homeostatic synaptic plasticity and contributes to the excitation/inhibition (E/I) balance under physiological conditions and upon pathological challenges. The purpose of this review is to discuss recent findings highlighting the significance of GABAA receptor heterogeneity for the concept of E/I balance and its relevance for epilepsy. Specifically, we address the following issues: (1) role for tonic inhibition, mediated by extrasynaptic GABAA receptors, for controlling neuronal excitability; (2) significance of chloride ion transport for maintenance of the E/I balance in adult brain; and (3) molecular mechanisms underlying GABAA receptor regulation (trafficking, posttranslational modification, gene transcription) that are important for homoeostatic plasticity. Finally, the relevance of these findings is discussed in light of the involvement of GABAA receptors in epileptic disorders, based on recent experimental studies of temporal lobe epilepsy (TLE) and absence seizures and on the identification of mutations in GABAA receptor subunit genes underlying familial forms of epilepsy

Role of dystrophin and utrophin for assembly and function of the dystrophin glycoprotein complex in non-muscle tissue

Abstract.: The dystrophin glycoprotein complex (DGC) is a multimeric protein assembly associated with either the X-linked cytoskeletal protein dystrophin or its autosomal homologue utrophin. In striated muscle cells, the DGC links the extracellular matrix to the actin cytoskeleton and mediates three major functions: structural stability of the plasma membrane, ion homeostasis, and transmembrane signaling. Mutations affecting the DGC underlie major forms of congenital muscle dystrophies. The DGC is prominent also in the central and peripheral nervous system and in tissues with a secretory function or which form barriers between functional compartments, such as the blood-brain barrier, choroid plexus, or kidney. A considerable molecular heterogeneity arises from cell-specific expression of its constituent proteins, notably short C-terminal isoforms of dystrophin. Experimentally, the generation of mice carrying targeted gene deletions affecting the DGC has clarified the interdependence of DGC proteins for assembly of the complex and revealed its importance for brain development and regulation of the 'milieu intérieur. Here, we focus on recent studies of the DGC in brain, blood-brain barrier and choroid plexus, retina, and kidney and discuss the role of dystrophin isoforms and utrophin for assembly of the complex in these tissue

Paisaje natural y actividades agrarias en el norte santafesino

Fil: Manzi, Rubén.Fil: Fritschy, Blanca

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

GABAA receptors form heteromeric GABA-gated chloride channels assembled from a large family of subunit genes. In cerebellum, distinct GABAA receptor subtypes, differing in subunit composition, are segregated between cell types and synaptic circuits. The cerebellum therefore represents a useful system to investigate the significance of GABAA receptor heterogeneity. For instance, studies of mice carrying targeted deletion of major GABAA receptor subunit genes revealed the role of α subunit variants for receptor assembly, synaptic targeting, and functional properties. In addition, these studies unraveled mandatory association between certain subunits and demonstrated distinct pharmacology of receptors mediating phasic and tonic inhibition. Although some of these mutants have a profound loss of GABAA receptors, they exhibit only minor impairment of motor function, suggesting activation of compensatory mechanisms to preserve inhibitory networks in the cerebellum. These adaptations include an altered balance between phasic and tonic inhibition, activation of voltage-independent K+ conductances, and upregulation of GABAA receptors in interneurons that are not affected directly by the mutation. Deletion of the α1 subunit gene leads to complete loss of GABAA receptors in Purkinje cells. A striking alteration occurs in these mice, whereby presynaptic GABAergic terminals are preserved in the molecular layer but make heterologous synapses with spines, characterized by a glutamatergic-like postsynaptic density. During development of α1% mice, GABAergic synapses are initially formed but are replaced upon spine maturation. These findings suggest that functional GABAA receptors are required for long-term maintenance of GABAergic synapses in Purkinje cell

Morocco and the Netherlands

This book on aspects of society, economy and culture in Morocco and the Netherlands contains contributions of 28 Moroccan and Dutch authors on religion, family and marriage law, local government and PJD, Abdelkrim, Morocco and the EU, drug trafficking, migration, youth, Dutch-Moroccan writers, and architecture, and focuses on the tension between tradition and modernity

Changes in the productive specialization of the northern rural-urban space of the city of Santa Fe, Argentina

El espacio rururbano –localizado al norte de la ciudad de Santa Fe– está constituido por los distritos Santa Fe, Recreo y Monte Vera. De vocación tradicionalmente hortícola este sector ecotonal atraviesa profundos cambios económicos, sociales y territoriales. Con el objeto de identificar las variaciones más significativas en las especializaciones productivas primarias se recurrió a los datos provistos por el IPEC (años 2003 a 2012) y al cálculo del cociente de localización. Este indicador expresa los niveles de concentración de actividades en unidades menores; en este caso los tres Distritos mencionados respecto al departamento La Capital. Con el apoyo de otras fuentes indirectas y directas (datos de entrevistas a horticultores y trabajo de reconocimiento a campo) se constató que la superficie destinada a la horticultura se ha reducido, que el cultivo de soja está en avance sustituyendo a las actividades tradicionales y que los usos del suelo residencial de baja densidad, el comercio y los servicios se están expandiendo hacia esa zona.The rural-urban space under study (located in the north of the city of Santa Fe) comprises the districts of Santa Fe, Recreo and Monte Vera. Traditionally horticultural, this ecotonal area is currently undergoing profound economic, social and territorial changes. With the aim of identifying the most significant variations in the primary productive specializations, data provided by IPEC (years 2003 to 2012) and the calculation of location quotient was resorted to. The location quotient is a measure of concentration of activities in smaller units; in this case, in the three districts abovementioned, as compared to La Capital Department. Other direct and indirect sources (data obtained from fieldwork and interviews done with horticulturists) have served to prove that surface destined to horticulture has lessened, soybean cultivation is both increasing and substituting traditional activities, and low intensity land uses such as residential, commercial and urban services are expanding towards this area.Fil: Fritschy, Blanca Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cardoso, María Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Reporting statistical methods and statistical results in EJN

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73132/1/j.1460-9568.2008.06581.x.pd

Molecular and functional heterogeneity of GABAergic synapses

Knowledge of the functional organization of the GABAergic system, the main inhibitory neurotransmitter system, in the CNS has increased remarkably in recent years. In particular, substantial progress has been made in elucidating the molecular mechanisms underlying the formation and plasticity of GABAergic synapses. Evidence available ascribes a key role to the cytoplasmic protein gephyrin to form a postsynaptic scaffold anchoring GABAA receptors along with other transmembrane proteins and signaling molecules in the postsynaptic density. However, the mechanisms of gephyrin scaffolding remain elusive, notably because gephyrin can auto-aggregate spontaneously and lacks PDZ protein interaction domains found in a majority of scaffolding proteins. In addition, the structural diversity of GABAA receptors, which are pentameric channels encoded by a large family of subunits, has been largely overlooked in these studies. Finally, the role of the dystrophin-glycoprotein complex, present in a subset of GABAergic synapses in cortical structures, remains ill-defined. In this review, we discuss recent results derived mainly from the analysis of mutant mice lacking a specific GABAA receptor subtype or a core protein of the GABAergic postsynaptic density (neuroligin-2, collybistin), highlighting the molecular diversity of GABAergic synapses and its relevance for brain plasticity and function. In addition, we discuss the contribution of the dystrophin-glycoprotein complex to the molecular and functional heterogeneity of GABAergic synapse

Molecular heterogeneity of the dystrophin-associated protein complex in the mouse kidney nephron: differential alterations in the absence of utrophin and dystrophin

The dystrophin-associated protein complex (DPC) consisting of syntrophin, dystrobrevin, and dystroglycan isoforms is associated either with dystrophin or its homolog utrophin. It is present not only in muscle cells, but also in numerous tissues, including kidney, liver, and brain. Using high-resolution immunofluorescence imaging and Western blotting, we have investigated the effects of utrophin and dystrophin gene deletion on the formation and membrane anchoring of the DPC in kidney epithelial cells, which co-express utrophin and low levels of the C-terminal dystrophin isoform Dp71. We show that multiple, molecularly distinct DPCs co-exist in the nephron; these DPCs have a segment-specific distribution and are only partially associated with utrophin in the basal membrane of tubular epithelial cells. In utrophin-deficient mice, a selective reduction of β2-syntrophin has been observed in medullary tubular segments, whereas α1-syntrophin and β1-syntrophin are retained, concomintant with an upregulation of β-dystroglycan, β-dystrobrevin, and Dp71. These findings suggest that β2-syntrophin is dependent on utrophin for association with the DPC, and that loss of utrophin is partially compensated by Dp71, allowing the preservation of the DPC in kidney epithelial cells. This hypothesis is confirmed by the almost complete loss of all DPC proteins examined in mice lacking full-length utrophin and all C-terminal dystrophin isoforms (utrophin0/0/mdx3Cv). The DPC thus critically depends on these proteins for assembly and/or membrane localization in kidney epithelial cell

"Biological failure” of the anterior cruciate ligament graft

Anterior cruciate ligament (ACL) reconstruction has the best chance for success when the graft undergoes extensive biologic remodeling and incorporation after implantation. There are many factors that can lead to graft failure and possible revision surgery. These include patient selection; surgical technique such as graft placement and tensioning; the use of allograft versus autograft; mechanical factors such as secondary restraint laxity; lack of a correct, carefully controlled post-operative rehabilitation program; and biological factors. When a patient presents with knee instability following ligament reconstruction and there is no history of a new trauma or identifiable technical error, biological failure should be considered. However, the biologic response of the grafted tissue is closely linked to the mechanical and biochemical environment into which the graft is placed. Thus, the "biological failure” of the ACL graft is a complex pathological entity whose cause is not fully understood. Failure may be initiated by early extensive graft necrosis, disturbances in revascularization, problems in cell repopulation and proliferation, and as well difficulties in the ligamentization process. However, further study of the biological characterization of a failed graft placed in a correct mechanical environment is warrante