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X-WR-CALDESC:Events for Bordeaux Neurocampus
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DTSTART;TZID=Europe/Paris:20251218T090000
DTEND;TZID=Europe/Paris:20251218T090000
DTSTAMP:20260511T163130
CREATED:20251119T113532Z
LAST-MODIFIED:20251119T125441Z
UID:189939-1766048400-1766048400@www.bordeaux-neurocampus.fr
SUMMARY:Thesis defense - Soukaina Es-Safi
DESCRIPTION:Venue: BBS \nDefense in french \n\nSoukaina ES-SAFI\nTeam: P3TN\nINCIA \nTitle\nRole of 5-HT4 receptors in the modulation of synaptic plasticity within the dentate gyrus \n\nAbstract\nCurrent antidepressant drugs (ADs) display limited efficacy and typically require a latency of three to six weeks before clinical improvement is observed. It has been demonstrated that increasing synaptic plasticity within the dentate gyrus (DG) of the hippocampus can induce a rapid and robust antidepressant effect. In this context\, serotonin type 4 receptor (5-HT4R) agonists have emerged as promising candidates for the development of fast-acting antidepressants. The aim of this thesis was to investigate the role of 5-HT4Rs in modulating hippocampal synaptic plasticity within the DG. However\, 5-HT4R agonists are known to enhance central serotonergic (5-HT) neuronal activity through “long-loop feedback” originating from the medial prefrontal cortex (mPFC)\, thereby indirectly stimulating other 5-HT receptor subtypes in the hippocampus\, including those expressed in the DG. To dissociate the direct effects of 5-HT4R activation within DG neurons from the indirect effects mediated by the mPFC\, we first developed a molecular biology tool based on short hairpin RNA (shRNA) expressed by lentiviral vectors (shRNA-LV)\, allowing for the inhibition of 5-HT4R expression specifically in the mPFC. This tool was validated using in vivo intracerebral microdialysis\, which demonstrated that 5-HT4R stimulation no longer induced an increase in hippocampal 5-HT release in animals injected with the shRNA-LV construct. Next\, using in vivo extracellular electrophysiology\, we examined the effects of the selective 5-HT4R agonist prucalopride on long-term potentiation (LTP) induced in the DG following high-frequency stimulation (HFS) of the perforant path (PP) in anesthetized rats. LTP was assessed by recording field potentials (FPs) and population spikes (PSs) from granule cells in the DG. Our results show that acute prucalopride treatment in naïve rats reduced the LTP success rate for both FPs and PSs compared to controls\, without significantly affecting LTP amplitude. In rats injected with shRNA-LV and acutely treated with prucalopride\, this reduction was restored to control levels for both FPs and PSs\, again without changes in LTP amplitude. Subchronic (three-day) prucalopride treatment in naïve rats once again reduced the LTP success rate for FPs without altering their amplitude. In contrast\, the PS success rate remained similar to that observed after acute treatment\, but PS amplitude was significantly and markedly decreased. In shRNA-LV–injected rats receiving the same subchronic treatment\, the LTP success rate for FPs was restored\, and a trend toward increased FP amplitude was observed compared to controls at the end of the recording period. Taken together\, these findings support the involvement of 5-HT4Rs in the modulation of synaptic plasticity within the DG. Activation of these receptors in the mPFC impairs LTP induction\, an effect that can be reversed by suppressing their expression. \nKeywords: Serotonin type 4 receptors\, long-term potentiation\, rapid-acting antidepressants\, medial prefrontal cortex\, dentate gyrus\, interfering RNA. \nJury\n\nM. CHAGRAOUI Abdeslam\, Université de Rouen\, Rapporteur M. MOULEDOUS Lionel\, Université de Toulouse\, RapporteurM. LUCAS Guillaume\, Université de Bordeaux\, Directeur de thèse\nM HADDJERI Nasser\, Université Claude Bernard Lyon 1\,  (membre invité)\nM. GUIARD Bruno\, Université de Toulouse\, Examinateur\nM. SPAMPINATO Umberto\, Université de Bordeaux\, Examinateur\n\n\n  \n
URL:https://www.bordeaux-neurocampus.fr/en/event/soutenance-de-these-soukaina-es-safi/
CATEGORIES:Thesis
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DTSTART;TZID=Europe/Paris:20251218T140000
DTEND;TZID=Europe/Paris:20251218T140000
DTSTAMP:20260511T163130
CREATED:20250708T071507Z
LAST-MODIFIED:20251124T190448Z
UID:185909-1766066400-1766066400@www.bordeaux-neurocampus.fr
SUMMARY:Thesis defense - Viviana Villicaña-Muñoz
DESCRIPTION:Venue : Centre Broca \n \n\nViviana Villicaña-Muñoz \nTeams:\nDynamic organization and function of synapses – IINS\nDopamine and neuronal assemblies – IMN \nTitle\nBasis of nanoscale function of neuromodulatory GPCRs inhibitory pathways in NMDAR-dependent LTD. \nAbstract\nLong-term potentiation (LTP) and long-term depression (LTD) are fundamental processes of synaptic plasticity that underlie long-lasting changes in synaptic strength. Together\, they form the cellular basis of learning and memory. The balance between these two forms of plasticity is essential during neuronal development\, as it refines synaptic connections and enables the emergence of efficient neuronal networks. During critical developmental periods\, LTD has been proposed to act as a signal-to-noise filter that enhances circuit efficiency through mechanisms such as synaptic pruning. One of the most prominent forms of LTD at excitatory synapses is mediated by N-methyl-D-aspartate receptors (NMDARs)\, which recruit intracellular signaling cascades leading to the downregulation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. Alongside these glutamatergic receptors\, excitatory synapses express a variety of highly sensitive G-protein-coupled receptors (GPCRs) that are activated by neuromodulatory inputs in key brain regions such as the hippocampus\, where they play a critical role in modulating synaptic plasticity. Understanding how these receptors interact is crucial for elucidating the mechanisms that tune synaptic physiology. \nIn my thesis\, I focused on the inhibitory Gi/o-coupled pathway (iGPCRs)—specifically dopaminergic\, serotonergic\, and histaminergic receptors—to explore the interplay between their intracellular signaling pathways and their potential synergistic interactions with NMDARs in inducing LTD in the hippocampus. First\, we established a causal relationship between NMDAR-dependent LTD and synaptic pruning through the chemical induction of LTD\, evidenced by electrophysiological and synaptic protein content analyses. Additionally\, we characterized the synaptic environments that render connections more susceptible to prune. I then examined whether subthreshold activation of NMDARs\, insufficient on its own to induce LTD\, could be potentiated through the synergistic activation of inhibitory GPCRs such as the dopaminergic D2 receptor (D2R)\, serotonergic 5-HT1A receptor\, and histaminergic H3 receptor. I found that D2R consistently synergized with NMDARs to restore LTD and promote synaptic pruning\, whereas this effect was not observed for the other GPCRs tested. Interestingly\, activation of D2R\, 5-HT1A\, and H3 receptors altered AMPA receptor current kinetics and induced synaptic pruning—effects that were partially reversed by subthreshold NMDAR activation in the serotonergic and histaminergic systems. These findings suggest that non-canonical pathways mediated by GPCR βγ subunits may interact intracellularly with NMDAR signaling. \nThe nanoscale organization of receptors has been shown to be a relevant marker for understanding synaptic transmission. Therefore\, in the second part of my research\, I employed direct stochastic optical reconstruction microscopy (dSTORM) to investigate the nanoscale organization of D2R. Using a Fab fragment targeting the extracellular loop of D2R\, I revealed that the receptors cluster within dendritic spine nanodomains and colocalize with postsynaptic markers. \nAltogether\, these results advance our understanding of the fine neuromodulatory control of LTD and structural plasticity. They highlight dopaminergic receptors as key modulators under conditions of NMDAR hypofunction during neurodevelopment\, suggesting that they could represent potential therapeutic targets in neurodevelopmental disorders such as certain forms of autism\, where these processes are disrupted. \nKey Words: Long-term-depression\, GCPR\, neuromodulation\, dopamine\, super resolution\, dopamine\, electrophysiology. \nJury\nSabine Levi\, Directrice de recherche Rapporteure\nMarianne Renner\, Professeur Rapporteure\nMarianne Benoit-Marand\, Pofesseur (associé) Examinatrice\nPierre Trifilieff\, Directeur de recherche Examinateur\nEric Hosy\, Chercheur Directeur de thèse\nJérôme Baufreton\, Directeur de recherche Co-directeur de thèse \n  \n
URL:https://www.bordeaux-neurocampus.fr/en/event/thesis-defense-viviana-villacana-munoz/
CATEGORIES:IMN,Thesis
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