| 1. |
- Becker, M, et al.
(författare)
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Presynaptic dysfunction in CASK-related neurodevelopmental disorders
- 2020
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 10:1, s. 312-
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Tidskriftsartikel (refereegranskat)abstract
- CASK-related disorders are genetically defined neurodevelopmental syndromes. There is limited information about the effects of CASK mutations in human neurons. Therefore, we sought to delineate CASK-mutation consequences and neuronal effects using induced pluripotent stem cell-derived neurons from two mutation carriers. One male case with autism spectrum disorder carried a novel splice-site mutation and a female case with intellectual disability carried an intragenic tandem duplication. We show reduction of CASK protein in maturing neurons from the mutation carriers, which leads to significant downregulation of genes involved in presynaptic development and of CASK protein interactors. Furthermore, CASK-deficient neurons showed decreased inhibitory presynapse size as indicated by VGAT staining, which may alter the excitatory–inhibitory (E/I) balance in developing neural circuitries. Using in vivo magnetic resonance spectroscopy quantification of GABA in the male mutation carrier, we further highlight the possibility to validate in vitro cellular data in the brain. Our data show that future pharmacological and clinical studies on targeting presynapses and E/I imbalance could lead to specific treatments for CASK-related disorders.
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| 2. |
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| 3. |
- Dore, R, et al.
(författare)
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Nesfatin-1 decreases the motivational and rewarding value of food
- 2020
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Ingår i: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. - : Springer Science and Business Media LLC. - 1740-634X. ; 45:1110, s. 1645-1655
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Tidskriftsartikel (refereegranskat)abstract
- Homeostatic and hedonic pathways distinctly interact to control food intake. Dysregulations of circuitries controlling hedonic feeding may disrupt homeostatic mechanisms and lead to eating disorders. The anorexigenic peptides nucleobindin-2 (NUCB2)/nesfatin-1 may be involved in the interaction of these pathways. The endogenous levels of this peptide are regulated by the feeding state, with reduced levels following fasting and normalized by refeeding. The fasting state is associated with biochemical and behavioral adaptations ultimately leading to enhanced sensitization of reward circuitries towards food reward. Although NUCB2/nesfatin-1 is expressed in reward-related brain areas, its role in regulating motivation and preference for nutrients has not yet been investigated. We here report that both dopamine and GABA neurons express NUCB2/nesfatin-1 in the VTA. Ex vivo electrophysiological recordings show that nesfatin-1 hyperpolarizes dopamine, but not GABA, neurons of the VTA by inducing an outward potassium current. In vivo, central administration of nesfatin-1 reduces motivation for food reward in a high-effort condition, sucrose intake and preference. We next adopted a 2-bottle choice procedure, whereby the reward value of sucrose was compared with that of a reference stimulus (sucralose + optogenetic stimulation of VTA dopamine neurons) and found that nesfatin-1 fully abolishes the fasting-induced increase in the reward value of sucrose. These findings indicate that nesfatin-1 reduces energy intake by negatively modulating dopaminergic neuron activity and, in turn, hedonic aspects of food intake. Since nesfatin-1´s actions are preserved in conditions of leptin resistance, the present findings render the NUCB2/nesfatin-1 system an appealing target for the development of novel therapeutical treatments towards obesity.
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| 4. |
- Reising, JP, et al.
(författare)
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Prostaglandin E2 Exerts Biphasic Dose Response on the PreBötzinger Complex Respiratory-Related Rhythm
- 2022
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Ingår i: Frontiers in neural circuits. - : Frontiers Media SA. - 1662-5110. ; 16, s. 826497-
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation in infants can cause respiratory dysfunction and is potentially life-threatening. Prostaglandin E2 (PGE2) is released during inflammatory events and perturbs breathing behavior in vivo. Here we study the effects of PGE2 on inspiratory motor rhythm generated by the preBötzinger complex (preBötC). We measured the concentration dependence of PGE2 (1 nM-1 μM) on inspiratory-related motor output in rhythmic medullary slice preparations. Low concentrations (1–10 nM) of PGE2 increased the duration of the inspiratory burst period, while higher concentrations (1 μM) decreased the burst period duration. Using specific pharmacology for prostanoid receptors (EP1-4R, FPR, and DP2R), we determined that coactivation of both EP2R and EP3R is necessary for PGE2 to modulate the inspiratory burst period. Additionally, biased activation of EP3 receptors lengthened the duration of the inspiratory burst period, while biased activation of EP2 receptors shortened the burst period. To help delineate which cell populations are affected by exposure to PGE2, we analyzed single-cell RNA-Seq data derived from preBötC cells. Transcripts encoding for EP2R (Ptger2) were differentially expressed in a cluster of excitatory neurons putatively located in the preBötC. A separate cluster of mixed inhibitory neurons differentially expressed EP3R (Ptger3). Our data provide evidence that EP2 and EP3 receptors increase the duration of the inspiratory burst period at 1–10 nM PGE2 and decrease the burst period duration at 1 μM. Further, the biphasic dose response likely results from differences in receptor binding affinity among prostanoid receptors.
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