J Neuroendocrinol

Pregnenolone is a steroid with specific characteristics, being the first steroid to be synthesised from cholesterol at all sites of steroidogenesis, including the brain. For many years, pregnenolone was defined as an inactive precursor of all steroids because no specific target had been discovered. However, over the last decade, it has become a steroid of interest because it has been recognised as being a biomarker for brain-related disorders through the development of metabolomic approaches and advanced analytical methods. In addition, physiological roles for pregnenolone emerged when specific targets were discovered. In this review, we highlight the discovery of the selective interaction of pregnenolone with the type-1 cannabinoid receptor (CB1R). After describing the specific characteristic of CB1Rs, we discuss the newly discovered mechanisms of their regulation by pregnenolone. In particular, we describe the action of pregnenolone as a negative allosteric modulator and a specific signalling inhibitor of the CB1R. These particular characteristics of pregnenolone provide a great strategic opportunity for therapeutic development in CB1-related disorders. Finally, we outline new perspectives using innovative genetic tools for the discovery of original regulatory mechanisms of pregnenolone on CB1-related functions

Cloning and Selective Expression in Brain and Kidney of ARNT2 Homologous to the Ah Receptor Nuclear Translocator (ARNT)

International audienceArnt2, a new member of the basic-helix-loop-helix transcription factor family, was cloned from rat brain cDNAs. Its deduced 712 amino acid sequence displays 63% identity with that of the aryl hydrocarbon receptor nuclear translocator (Arnt1) that was completely established. Whereas Arnt2 gene expression, established by Northern blotting and in situ hybridization histochemistry, occurred selectively in brain and kidney, that of Arnt1 was ubiquitous, suggesting that the two proteins play distinct roles, presumably via dimerization and DNA binding with different partners

Serotonin2B receptors in the rat dorsal raphe nucleus exert a GABA-mediated tonic inhibitory control on serotonin neurons

The central serotonin2B receptor (5-HT2BR) is a well-established modulator of dopamine (DA) neuron activity in the rodent brain. Recent studies in rats have shown that the effect of 5-HT2BR antagonists on accumbal and medial prefrontal cortex (mPFC) DA outflow results from a primary action in the dorsal raphe nucleus (DRN), where they activate 5-HT neurons innervating the mPFC. Although the mechanisms underlying this interaction remain largely unknown, data in the literature suggest the involvement of DRN GABAergic interneurons in the control of 5-HT activity. The present study examined this hypothesis using in vivo (intracerebral microdialysis) and in vitro (immunohistochemistry coupled to reverse transcription-polymerase chain reaction) experimental approaches in rats. Intraperitoneal (0.16 mg/kg) or intra-DRN (1 μM) administration of the selective 5-HT2BR antagonist RS 127445 increased 5-HT outflow in both the DRN and the mPFC, these effects being prevented by the intra-DRN perfusion of the GABAA antagonist bicuculline (100 μM), as well as by the subcutaneous (0.16 mg/kg) or the intra-DRN (0.1 μM) administration of the selective 5-HT1AR antagonist WAY 100635. The increase in DRN 5-HT outflow induced by the intra-DRN administration of the selective 5-HT reuptake inhibitor citalopram (0.1 μM) was potentiated by the intra-DRN administration (0.5 μM) of RS 127445 only in the absence of bicuculline perfusion. Finally, in vitro experiments revealed the presence of the 5-HT2BR mRNA on DRN GABAergic interneurons. Altogether, these results show that, in the rat DRN, 5-HT2BRs are located on GABAergic interneurons, and exert a tonic inhibitory control on 5-HT neurons innervating the mPFC.This study was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and Bordeaux University and by grant SAF2015-68346-P from the Spanish Ministry of Economy and Competitiveness.Peer reviewe

Multimodal Outcome at 7 Years of Age after Neonatal Arterial Ischemic Stroke

To evaluate the epileptic, academic, and developmental status at age 7 years in a large population of term-born children who sustained neonatal arterial ischemic stroke (NAIS), and to assess the co-occurrence of these outcomes

Discovery of Naturally Occurring Splice Variants of the Rat Histamine H 3 Receptor That Act as Dominant-Negative Isoforms

ABSTRACT We described previously the cDNA cloning of three functional rat histamine H 3 receptor (rH 3 R) isoforms as well as the differential brain expression patterns of their corresponding mRNAs and signaling properties of the resulting rH 3A , rH 3B , and rH 3C receptor isoforms (Mol Pharmacol 59:1-8). In the current report, we describe the cDNA cloning, mRNA localization in the rat central nervous system, and pharmacological characterization of three additional rH 3 R splice variants (rH 3D , rH 3E , and rH 3F ) that differ from the previously published isoforms in that they result from an additional alternative-splicing event. These new H 3 R isoforms lack the seventh transmembrane (TM) helix and contain an alternative, putatively extracellular, C terminus (6TM-rH 3 isoforms). After heterologous expression in COS-7 cells, radioligand binding or functional responses upon the application of various H 3 R ligands could not be detected for the 6TM-rH 3 isoforms. In contrast to the rH 3A receptor (rH 3A R), detection of the rH 3D isoform using hemagglutinin antibodies revealed that the rH 3D isoform remains mainly intracellular. The expression of the rH 3D-F splice variants, however, modulates the cell surface expression-levels and subsequent functional responses of the 7TM H 3 R isoforms. Coexpression of the rH 3A R and the rH 3D isoforms resulted in the intracellular retention of the rH 3A R and reduced rH 3A R functionality. Finally, we show that in rat brain, the H 3 R mRNA expression levels are modulated upon treatment with the convulsant pentylenetetrazole, suggesting that the rH 3 R isoforms described herein thus represent a novel physiological mechanism for controlling the activity of the histaminergic system

Differential expression of the neuronal CB1 cannabinoid receptor in the hippocampus of male Ts65Dn Down syndrome mouse model

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Association of transcallosal motor fibres with function of both hands after unilateral neonatal arterial ischemic stroke

International audienceAIM: The objective of this study was to investigate the involvement of the motor fibres of the corpus callosum after unilateral neonatal arterial ischemic stroke (NAIS) of the middle cerebral artery territory and the relationship to both ipsilesional and contralesional hand function.METHOD: Using high-resolution structural magnetic resonance imaging (MRI), functional MRI, and magnetic resonance diffusion-tractography, we compared the midsagittal area of the motor part of the corpus callosum (defined by the fibres connecting the precentral gyri) between 33 7-year-old children after unilateral NAIS and 31 typically developing 7-year-old children. Hand motor performance was assessed by the box and blocks test.RESULTS: Children after NAIS showed on average significantly smaller motor corpus callosum area compared to typically developing children (p|t|)=0.034) and ipsilesional hand motor performance (Pr(>|t|)=0.006) after controlling for lesion volume and sex. In a post-hoc analysis the additional contribution of corticospinal tract damage was evaluated.INTERPRETATION: Compared to typically developing children, children after NAIS exhibited a smaller motor part of their corpus callosum associated with reduced contralesional but also ipsilesional manual dexterity. These results indicate that the affection of transcallosal motor fibres in unilateral NAIS might be of functional relevance and an important part of the involved structural network that should be elucidated in further studies.TRIAL REGISTRATION: ClinicalTrials.gov NCT02511249.© 2017 Mac Keith Press

Multimodal Outcome at 7 Years of Age after Neonatal Arterial Ischemic Stroke

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Manual dexterity, but not cerebral palsy, predicts cognitive functioning after neonatal stroke

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