Gut colonization by Proteobacteria alters host metabolism and modulates cocaine neurobehavioral responses

Gut-microbiota membership is associated with diverse neuropsychological outcomes, including substance use disorders (SUDs). Here, we use mice colonized with Citrobacter rodentium or the human γ-Proteobacteria commensal Escherichia coli HS as a model to examine the mechanistic interactions between gut microbes and host responses to cocaine. We find that cocaine exposure increases intestinal norepinephrine levels that are sensed through the bacterial adrenergic receptor QseC to promote intestinal colonization of γ-Proteobacteria. Colonized mice show enhanced host cocaine-induced behaviors. The neuroactive metabolite glycine, a bacterial nitrogen source, is depleted in the gut and cerebrospinal fluid of colonized mice. Systemic glycine repletion reversed, and γ-Proteobacteria mutated for glycine uptake did not alter the host response to cocaine. γ-Proteobacteria modulated glycine levels are linked to cocaine-induced transcriptional plasticity in the nucleus accumbens through glutamatergic transmission. The mechanism outline here could potentially be exploited to modulate reward-related brain circuits that contribute to SUDs.Fil: Cuesta, Santiago. University of Texas. Southwestern Medical Center; Estados UnidosFil: Burdisso, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Segev, Amir. University Of Texas Southwestern Medical School,; Estados Unidos. University of Texas; Estados UnidosFil: Kourrich, Saïd. Université du Québec a Montreal; CanadáFil: Sperandio, Vanessa. University of Texas. Southwestern Medical Center; Estados Unido

Postsynaptic Signals Mediating Induction of Long-Term Synaptic Depression in the Entorhinal Cortex

The entorhinal cortex receives a large projection from the piriform cortex, and synaptic plasticity in this pathway may affect olfactory processing. In vitro whole cell recordings have been used here to investigate postsynaptic signalling mechanisms that mediate the induction of long-term synaptic depression (LTD) in layer II entorhinal cortex cells. To induce LTD, pairs of pulses, using a 30-millisecond interval, were delivered at 1 Hz for 15 minutes. Induction of LTD was blocked by the NMDA receptor antagonist APV and by the calcium chelator BAPTA, consistent with a requirement for calcium influx via NMDA receptors. Induction of LTD was blocked when the FK506 was included in the intracellular solution to block the phosphatase calcineurin. Okadaic acid, which blocks activation of protein phosphatases 1 and 2a, also prevented LTD. Activation of protein phosphatases following calcium influx therefore contributes to induction of LTD in layer II of the entorhinal cortex

Rôle des canaux Kv1.1 et Kv1.3 au cours des processus mnésiques chez le rat

Les expériences rapportées dans ce mémoire avaient pour but d'étudier le rôle des canaux KV1.1 et KV1.3 au cours des processus d'apprentissage et de mémoire. Dans la première approche (comportementale), l'effet du blocage de ces canaux par la KTX (10 ng) (en injection icv) a été évalué dans différents protocoles mettant en jeu préférentiellement deux types de mémoire dans une tâche de discrimination olfactive : la mémoire procédurale et la mémoire de référence. Dans les deux types de mémoire étudiée, le blocage de ces canaux par la KTX facilitait l'apprentissage et non la consolidation des informations. Cette toxine facilitait également le rappel à long-terme d'une association odeur-renforcement. Une expérience contrôle en open-field a montré que le blocage des canaux KV1.1 et KV1.3 par la KTX n'affectait pas les processus d'attention. La deuxième approche (électrophysiologique) avait pour but d'explorer les éventuels phénomènes de plasticité pouvant sous-tendre la facilitation de l'apprentissage induit par la KTX. Une première expérience, "in vitro" sur tranche d'hippocampe, a montré que la KTX (100 nM) induisait une facilitation synaptique de longue durée vraisemblablement par un mécanisme pré-synaptique au niveau des synapses fibres moussues-CA3. Ce résultat a été ensuite confirmé par une expérience réalisée "in vivo" chez le rat éveillé libre de ses mouvements avec une dose de 10 ng en icv. La troisième approche (histochimique) avait pour but d'observer une éventuelle implication de ces canaux au cours des processus mnésiques. La technique d'hybridation in situ a montré une diminution de l'expression des ARNm KV1.1 au niveau de l'hippocampe ventral (GD, CA3 et CA1) lorsque les rats étaient sacrifiés 1 heure après la seconde séance d'apprentissage d'une association odeur-renforcement. D'autres variations ont été observées, mais ne semblaient pas être spécifiques du conditionnement.AIX-MARSEILLE1-BU Sci.St Charles (130552104) / SudocSudocFranceF

Transient hippocampal down-regulation of Kv1.1 subunit mRNA during associative learning in rats

Voltage-gated potassium channels (Kv) are critically involved in learning and memory processes. It is not known, however, whether the expression of the Kv1.1 subunit, constituting Kv1 channels, can be specifically regulated in brain areas important for learning and memory processing. Radioactive in situ hybridization was used to evaluate the content of Kv1.1 α-subunit mRNA in the olfactory bulb, ventral, and dorsal hippocampus at different stages of an odor-discrimination associative task in rats. Naive, conditioned, and pseudoconditioned animals were sacrificed at different times either prior to a two-odor significance learning or after odor discrimination was established. Important decreases of Kv1.1 mRNA levels were transiently observed in the ventral hippocampus before successful learning when compared with the pseudoconditioned group. Moreover, temporal group analysis showed significant labeling alterations in the hippocampus of conditioned and pseudoconditioned groups throughout the training. Finally, Kv1.1 mRNA levels in the hippocampus were positively correlated with odor-reward association learning in rats that were beginning to discriminate between odors. These findings indicate that the Kv1.1 subunit is transiently down-regulated in the early stages of learning and suggest that Kv1 channel expression regulation is critical for the modification of neuronal substrates underlying new information acquisition

RNF13 Dileucine Motif Variants L311S and L312P Interfere with Endosomal Localization and AP-3 Complex Association

Developmental and epileptic encephalopathies (DEE) are rare and serious neurological disorders characterized by severe epilepsy with refractory seizures and a significant developmental delay. Recently, DEE73 was linked to genetic alterations of the RNF13 gene, which convert positions 311 or 312 in the RNF13 protein from leucine to serine or proline, respectively (L311S and L312P). Using a fluorescence microscopy approach to investigate the molecular and cellular mechanisms affected by RNF13 protein variants, the current study shows that wild-type RNF13 localizes extensively with endosomes and lysosomes, while L311S and L312P do not extensively colocalize with the lysosomal marker Lamp1. Our results show that RNF13 L311S and L312P proteins affect the size of endosomal vesicles along with the temporal and spatial progression of fluorescently labeled epidermal growth factor, but not transferrin, in the endolysosomal system. Furthermore, GST-pulldown and co-immunoprecipitation show that RNF13 variants disrupt association with AP-3 complex. Knockdown of AP-3 complex subunit AP3D1 alters the lysosomal localization of wild-type RNF13 and similarly affects the size of endosomal vesicles. Importantly, our study provides a first step toward understanding the cellular and molecular mechanism altered by DEE73-associated genetic variations of RNF13

Overview of Sigma-1R Subcellular Specific Biological Functions and Role in Neuroprotection

For the past several years, fundamental research on Sigma-1R (S1R) protein has unveiled its necessity for maintaining proper cellular homeostasis through modulation of calcium and lipid exchange between the endoplasmic reticulum (ER) and mitochondria, ER-stress response, and many other mechanisms. Most of these processes, such as ER-stress response and autophagy, have been associated with neuroprotective roles. In fact, improving these mechanisms using S1R agonists was beneficial in several brain disorders including neurodegenerative diseases. In this review, we will examine S1R subcellular localization and describe S1R-associated biological activity within these specific compartments, i.e., the Mitochondrion-Associated ER Membrane (MAM), ER–Lipid Droplet (ER–LD) interface, ER–Plasma Membreane (ER–PM) interface, and the Nuclear Envelope (NE). We also discussed how the dysregulation of these pathways contributes to neurodegenerative diseases, while highlighting the cellular mechanisms and key binding partners engaged in these processes