La importancia del fin, causa de las causas. Hacia una teología viva y contemplativa en la escuela de Santo Tomás

En el pensamiento moderno las ciencias exactas y las matemáticas han llegado a desplazar a la filosofía como lugar de conocimiento verdadero. Si la teología no quiere quedarse en un fideísmo necesita de una filosofía firme como la que ofi'ece, por ejemplo, Santo Tomás de Aquino. Redescubrir a Santo Tomás de Aquino supone entender el «fin» como «causa causarum», como «causa de las causas». Eso es lo que descubrió Santo Tomás en Aristóteles y lo que olvidó la escolástica posterior, al entender esta noción de causa únicamente de manera metafórica. El artículo examina cómo este principio ilumina las partes de la Suma Teológica que Santo Tomás dedica a Dios, Uno y Trino, y a nuestro conocimiento de Dios, a la creación, a la gracia, etc

Implication du transporteur potassium / chlore KCC2 dans la rythmopathie hippocampique

In the CNS, synaptic release of GABA neurotransmitter is mainly responsible for fast inhibitory transmission. This is mediated by chloride flow through GABAARs. Hence, tight control of chloride homeostasis is critical for maintenance of the efficacy of GABAergic transmission. In mature neurons, this is primarily achieved by the activity of the potassium – chloride transporter KCC2 which extrudes chloride from the cells. Expression of KCC2 is compromised in numerous neurological disorders including epilepsy, Rett syndrome or neuropathic pain. Subsequent alterations of GABAergic signaling through accumulation of intraneuronal chloride are thought to underlie many of the pathological symptoms observed in these conditions. However, KCC2 is also highly expressed in the vicinity of glutamatergic synapses where it plays a major role in controling the efficacy of glutamatergic transmission and gates long-term potentiation of excitatory synapses. Remarkably, these functions did not depend on chloride transport but rather on KCC2 interaction with several protein partners. Hence, KCC2 can be classified as a moonlightning protein with multiple functions at excitatory and inhibitory synapses. This complicates predictions of the overall effect of its suppression on a neuronal network. During my PhD, I characterized the effects of KCC2 downregulation in dentate granule cells at the cellular, synaptic and network levels. Unexpectedly, lack of KCC2 did not impact steady-state GABAergic transmission. In contrast, my work shed light on a novel critical role of KCC2 in controling neuronal excitability through its interaction with the leak-potassium channel Task-3. This in turn alters hippocampal rhythmogenesis. My results thus described a novel mechanism through which KCC2 influence neuronal activity indepently of its transport function. They predict that deficits associated with KCC2 downregulation may be at least partly explained by regulation of cell excitability and point to Task-3 as a new potential therapeutic target in the treatment of these pathologies.Dans le système nerveux central, la transmission inhibitrice est principalement assurée par le relargage du neurotransmetteur GABA dans la fente synaptique. La fixation du GABA sur les récepteurs GABAA induit en effet un flux entrant d’ions chlorure, résultant en une hyperpolarisation du neurone. Le maintien d’une faible concentration intraneuronale en chlore est donc essentielle à l’action inhibitrice du GABA. Dans les neurones matures, cette fonction est principalement réalisée grâce à l’activité du transporteur potassium – chlore KCC2 qui exporte en permanence les ions chlorures. Dans de nombreuses pathologies neurologiques, telles que l’épilepsie, le syndrome de Rett ou encore les douleurs neuropathiques, on observe une diminution de l’expression de KCC2. Cela conduit à une élévation du niveau de chlore intraneuronal et à une altération de la transmission GABAergique. Cet effet est supposé être à la base de nombre des symptômes observés dans les pathologies citées précédemment. Cependant, KCC2 est également fortement exprimé à proximité des synapses glutamatergiques. Sa présence influence ainsi l’efficacité de la transmission excitatrice et est nécessaire à l’expression de la potentialisation à long terme des synapses. Ces fonctions inattendues de KCC2 aux synapses excitatrice ne reposent pas sur sa fonction de transport de chlore mais plutôt sur ses interactions avec diverses protéines. Ainsi, le transporteur KCC2 possède de multiple fonctions et régule différemment les transmissions excitatrice et inhibitrice. Prédire l’effet de la perte du transporteur sur l’activité globale d’un réseau neuronal est donc compliqué. Durant ma thèse, j’ai caractérisé les effets de la suppression de KCC2 dans les cellules en grains du gyrus denté sur leurs propriétés cellulaires, synaptiques et sur l’activité du réseau hippocampique. De façon inattendue, j’ai montré que la perte de KCC2 ne s’accompagnait pas de modifications majeures de la transmission inhibitrice. En revanche, j’ai mis en évidence un nouveau mécanisme indépendant du transport de chlore par lequel KCC2 contrôle l’excitabilité des neurones et la rythmogénèse hippocampique à travers son interaction avec le canal potassique Task-3. Mes résultats prédisent que les déficits associés à une perte de KCC2 pourraient être en partie expliqués par cet effet sur l’excitabilité. Ils suggèrent également que Task-3 pourrait constituer une nouvelle cible thérapeutique dans le traitement de ces pathologies

Hegel : l'intelligence de la foi ? / Marie-Pierre Goutierre

Collection : AletheiaContient une table des matièresAvec mode text

Hippocampo-cortical coupling mediates memory consolidation during sleep

International audienc

Silencing KCC2 in mouse dorsal hippocampus compromises spatial and contextual memory

International audienceDelayed upregulation of the neuronal chloride extruder KCC2 underlies the progressive shift in GABA signaling polarity during development. Conversely, KCC2 downregulation is observed in a variety of neurological and psychiatric disorders often associated with cognitive impairment. Reduced KCC2 expression and function in mature networks may disrupt GABA signaling and promote anomalous network activities underlying these disorders. However, the causal link between KCC2 downregulation, altered brain rhythmogenesis and cognitive function remains elusive. Here, by combining behavioral exploration with in vivo electrophysiology we assessed the impact of chronic KCC2 downregulation in mouse dorsal hippocampus and showed it compromises both spatial and contextual memory. This was associated with altered hippocampal rhythmogenesis and neuronal hyperexcitability, with increased CA1 pyramidal cell burst firing during non-REM sleep. Reducing neuronal excitability with terbinafine, a specific Task-3 leak potassium channel opener, occluded the impairment of contextual memory upon KCC2 knockdown. Our results establish a causal relationship between KCC2 expression and cognitive performance and suggest that non-epileptiform rhythmopathies and neuronal hyperexcitability are central to the deficits caused by KCC2 downregulation in the adult mouse brain

La géphyrine interagit avec le co-transporteur K-Cl KCC2 pour réguler son expression de surface et sa fonction dans les neurones corticaux.

International audienceThe K+-Cl- cotransporter KCC2, encoded by the Slc12a5 gene, is a neuron-specific chloride extruder that tunes the strength and polarity of GABAA receptor-mediated transmission. In addition to its canonical ion transport function, KCC2 also regulates spinogenesis and excitatory synaptic function through interaction with a variety of molecular partners. KCC2 is enriched in the vicinity of both glutamatergic and GABAergic synapses, the activity of which in turn regulates its membrane stability and function. KCC2 interaction with the submembrane actin cytoskeleton via 4.1N is known to control its anchoring near glutamatergic synapses on dendritic spines. However, the molecular determinants of KCC2 clustering near GABAergic synapses remain unknown. Here, we used proteomics to identify novel KCC2 interacting proteins in the adult rat neocortex. We identified both known and novel candidate KCC2 partners, including some involved in neuronal development and synaptic transmission. These include gephyrin, the main scaffolding molecule at GABAergic synapses. Gephyrin interaction with endogenous KCC2 was confirmed by immunoprecipitation from rat neocortical extracts. We showed that gephyrin stabilizes plasmalemmal KCC2 and promotes its clustering in hippocampal neurons, mostly but not exclusively near GABAergic synapses, thereby controlling KCC2-mediated chloride extrusion. This study identifies gephyrin as a novel KCC2 anchoring molecule that regulates its membrane expression and function in cortical neurons.SIGNIFICANCE STATEMENT Fast synaptic inhibition in the brain is mediated by chloride-permeable GABAA receptors (GABAARs) and therefore relies on transmembrane chloride gradients. In neurons, these gradients are primarily maintained by the K/Cl cotransporter KCC2. Therefore, understanding the mechanisms controlling KCC2 expression and function is crucial to understand its physiological regulation and rescue its function in the pathology. KCC2 function depends on its membrane expression and clustering, but the underlying mechanisms remain unknown. We describe the interaction between KCC2 and gephyrin, the main scaffolding protein at inhibitory synapses. We show that gephyrin controls plasmalemmal KCC2 clustering and that loss of gephyrin compromises KCC2 function. Our data suggest functional units comprising GABAARs, gephyrin, and KCC2 act to regulate synaptic GABA signaling

KCC2 Regulates Neuronal Excitability and Hippocampal Activity via Interaction with Task-3 Channels

International audienceKCC2 regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in numerous neurological and psychiatric disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity underlying the pathology. We tested this hypothesis and explored the functional impact of chronic KCC2 downregulation in the rat dentate gyrus. Although the reversal potential of GABAA receptor currents is depolarized in KCC2 knockdown neurons, this shift is compensated by depolarization of the resting membrane potential. This reflects downregulation of leak potassium currents. We show KCC2 interacts with Task-3 (KCNK9) channels and is required for their membrane expression. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis, which could be normalized by chemogenetic hyperpolarization. Our data reveal KCC2 downregulation engages complex synaptic and cellular alterations beyond GABA signaling that perturb network activity thus offering additional targets for therapeutic intervention

Mutation of the α-tubulin Tuba1a leads to straighter microtubules and perturbs neuronal migration

International audienc

First Electron Beam of the ThomX Project

International audienceThe ThomX accelerator beam commissioning phase is now ongoing. The 50 MeV electron accelerator complex consists of a 50 MeV linear accelerator and a pulsed mode ring. It is dedicated to the production of X-rays by Compton backscattering. The performance of the beam at the interaction point is demanding in terms of emittance, charge, energy spread and transverse size. The choice of an undamped ring in pulsed mode also stresses the performance of the beam from the linear accelerator. Thus, commissioning includes a beam based alignment and a simulation/experimental matching procedure to reach the X-ray beam requirements. We will present the first 50 MeV electron beam obtained with ThomX and its characteristics