Wnt signalling tunes neurotransmitter release by directly targeting Synaptotagmin-1

The functional assembly of the synaptic release machinery is well understood; however, how signalling factors modulate this process remains unknown. Recent studies suggest that Wnts play a role in presynaptic function. To examine the mechanisms involved, we investigated the interaction of release machinery proteins with Dishevelled-1 (Dvl1), a scaffold protein that determines the cellular locale of Wnt action. Here we show that Dvl1 directly interacts with Synaptotagmin-1 (Syt-1) and indirectly with the SNARE proteins SNAP25 and Syntaxin (Stx-1). Importantly, the interaction of Dvl1 with Syt-1, which is regulated by Wnts, modulates neurotransmitter release. Moreover, presynaptic terminals from Wnt signalling-deficient mice exhibit reduced release probability and are unable to sustain high-frequency release. Consistently, the readily releasable pool size and formation of SNARE complexes are reduced. Our studies demonstrate that Wnt signalling tunes neurotransmitter release and identify Syt-1 as a target for modulation by secreted signalling proteins.Fil: Ciani, Lorenza. University College London; Estados UnidosFil: Marzo, Aude. University College London; Estados UnidosFil: Boyle, Kieran. University College London; Estados UnidosFil: Stamatakou, Eleanna. University College London; Estados UnidosFil: Lopes, Douglas M.. University College London; Estados UnidosFil: Anane, Derek. University College London; Estados UnidosFil: McLeod, Faye. University College London; Estados UnidosFil: Rosso, Silvana Beatriz. University College London; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gibb, Alasdair. University College London; Estados UnidosFil: Salinas, Patricia C.. University College London; Estados Unido

Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus

Synapse degeneration occurs early in neurodegenerative diseases and correlates strongly with cognitive decline in Alzheimer's disease (AD). The molecular mechanisms that trigger synapse vulnerability and those that promote synapse regeneration after substantial synaptic failure remain poorly understood. Increasing evidence suggests a link between a deficiency in Wnt signaling and AD. The secreted Wnt antagonist Dickkopf-1 (Dkk1), which is elevated in AD, contributes to amyloid-β-mediated synaptic failure. However, the impact of Dkk1 at the circuit level and the mechanism by which synapses disassemble have not yet been explored. Using a transgenic mouse model that inducibly expresses Dkk1 in the hippocampus, we demonstrate that Dkk1 triggers synapse loss, impairs long-term potentiation, enhances long-term depression, and induces learning and memory deficits. We decipher the mechanism involved in synapse loss induced by Dkk1 as it can be prevented by combined inhibition of the Gsk3 and RhoA-Rock pathways. Notably, after loss of synaptic connectivity, reactivation of the Wnt pathway by cessation of Dkk1 expression completely restores synapse number, synaptic plasticity, and long-term memory. These findings demonstrate the remarkable capacity of adult neurons to regenerate functional circuits and highlight Wnt signaling as a targetable pathway for neuronal circuit recovery after synapse degeneration

Effects of noradrenaline on glutamatergic synaptic transmission in rat prefrontal cortex

Le cortex préfrontal (PFC) est le siège des fonctions cognitives supérieures et la noradrénaline (NA) peut être largement libérée dans le PFC pendant un stress. Nous avons testé l'effet de la noradrénaline (20 M) sur la transmission synaptique glutamatergique dans le PFC chez le rat, par enregistrements intracellulaires in vitro des neurones pyramidaux de la couche V de ce cortex. L'application dans le bain de NA induit une dépression synaptique aigue du potentiel postsynaptique excitateur lors de la stimulation des fibres afférentes des couches I-II qui est suivie d'une dépression à long-terme. Cette LTD est sélective et dépend de la concentration de NA. La LTD nécessite l'activation des récepteurs alpha1 et 2 adrénergiques, NMDA, PKC et ERK1/2. L'exposition préalable des animaux à un stress de rétention bloque la LTD in vitro. Des études comportementales préliminaires, menées sur l'impact de ce stress, montre que ce stress pourrait promouvoir de meilleures performances dans certaines conditions. La LTD induite par la NA dans le PFC pourrait être occasionnée par le stress qui serait positif et favoriserait une plus grande flexibilité cognitive.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Oxidative Stress and Emergence of Psychosis

Treatment and prevention strategies for schizophrenia require knowledge about the mechanisms involved in the psychotic transition. Increasing evidence suggests a redox imbalance in schizophrenia patients. This narrative review presents an overview of the scientific literature regarding blood oxidative stress markers’ evolution in the early stages of psychosis and chronic patients. Studies investigating peripheral levels of oxidative stress in schizophrenia patients, first episode of psychosis or UHR individuals were considered. A total of 76 peer-reviewed articles published from 1991 to 2022 on PubMed and EMBASE were included. Schizophrenia patients present with increased levels of oxidative damage to lipids in the blood, and decreased levels of non-enzymatic antioxidants. Genetic studies provide evidence for altered antioxidant functions in patients. Antioxidant blood levels are decreased before psychosis onset and blood levels of oxidative stress correlate with symptoms severity in patients. Finally, adjunct treatment of antipsychotics with the antioxidant N-acetyl cysteine appears to be effective in schizophrenia patients. Further studies are required to assess its efficacy as a prevention strategy. Redox imbalance might contribute to the pathophysiology of emerging psychosis and could serve as a therapeutic target for preventive or adjunctive therapies, as well as biomarkers of disease progression

Dysregulation of peripheral expression of the YWHA genes during conversion to psychosis

International audienceThe seven human 14-3-3 proteins are encoded by the YWHA-gene family. They are expressed in the brain where they play multiple roles including the modulation of synaptic plasticity and neuronal development. Previous studies have provided arguments for their involvement in schizophrenia, but their role during disease onset is unknown. We explored the peripheral-blood expression level of the seven YWHA genes in 92 young individuals at ultra-high risk for psychosis (UHR). During the study, 36 participants converted to psychosis (converters) while 56 did not (non-converters). YWHA genes expression was evaluated at baseline and after a mean follow-up of 10.3 months using multiplex quantitative PCR. Compared with non-converters, the converters had a significantly higher baseline expression levels for 5 YWHA family genes, and significantly different longitudinal changes in the expression of YWHAE, YWHAG, YWHAH, YWHAS and YWAHZ. A principal-component analysis also indicated that the YWHA expression was significantly different between converters and non-converters suggesting a dysregulation of the YWHA co-expression network. Although these results were obtained from peripheral blood which indirectly reflects brain chemistry, they indicate that this gene family may play a role in psychosis onset, opening the way to the identification of prognostic biomarkers or new drug targets

Wnt Signaling Mediates LTP-Dependent Spine Plasticity and AMPAR Localization through Frizzled-7 Receptors

Summary: The structural and functional plasticity of synapses is critical for learning and memory. Long-term potentiation (LTP) induction promotes spine growth and AMPAR accumulation at excitatory synapses, leading to increased synaptic strength. Glutamate initiates these processes, but the contribution from extracellular modulators is not fully established. Wnts are required for spine formation; however, their impact on activity-mediated spine plasticity and AMPAR localization is unknown. We found that LTP induction rapidly increased synaptic Wnt7a/b protein levels. Acute blockade of endogenous Wnts or loss of postsynaptic Frizzled-7 (Fz7) receptors impaired LTP-mediated synaptic strength, spine growth, and AMPAR localization at synapses. Live imaging of SEP-GluA1 and single-particle tracking revealed that Wnt7a rapidly promoted synaptic AMPAR recruitment and trapping. Wnt7a, through Fz7, induced CaMKII-dependent loss of SynGAP from spines and increased extrasynaptic AMPARs by PKA phosphorylation. We identify a critical role for Wnt-Fz7 signaling in LTP-mediated synaptic accumulation of AMPARs and spine plasticity. : McLeod et al. reveal that Wnt7a-Fz7 signaling is required for LTP-mediated spine plasticity, AMPAR localization, and synaptic strength through the activation of the CaMKII, ERK, and PKA pathways. Their findings demonstrate that extracellular Wnt proteins are crucial upstream initiators of LTP-mediated structural and function synaptic plasticity. Keywords: Wnt signaling, synaptic plasticity, spine plasticity, LTP, AMPA receptors, Frizzled-7, Sfrp