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Synaptic Circuits of Memory

Team Leader : Christophe Mulle

Christophe Mulle is a research director (DRCE) at the CNRS and University of Bordeaux. He is a cellular neurobiologist with expertise in glutamate receptors, electrophysiology of synaptic transmission and neuronal circuits in the context of memory encoding. After being trained in the labs of Jean-Pierre Changeux at the Pasteur Institute and Steve Heinemann at the Salk Institute in San Diego, he created a CNRS laboratory in Bordeaux in 1995.The research carried out in the group headed by Christophe Mulle ambitions to link cell biological mechanisms of protein trafficking and function to synaptic physiology and dysfunction. In 2014, he has received the Grand Prix Lamonica de Neurologie of the French Academy of Science.

Team 2020

General objective

The main objective of the team is to link synaptic function and plasticity to the activity of cortical and hippocampal circuits during behaviour, in physiological and pathological conditions.

The group explores the mechanisms and role of presynaptic plasticity, and the operation of hippocampal circuits in the context of episodic-like memory encoding. Great efforts are made to develop methods for interrogating the connectivity and function of local circuits in vivo in behavioural conditions. The group has developed viral toolkits to combine gene manipulation and optogenetic activation of selected neuronal populations, as well as novel strategies to label engram neurons. Electrophysiological methods used to analyze synapses and circuits span from ex vivo recordings to in vivo patch-clamp and silicone probe recordings to capture single cell and neuronal ensemble activity in awake mice.

We explore the mechanisms and consequences of synaptic dysfunction (synaptopathies) in Alzheimer’s disease. We postulate that synaptic pathology in AD includes a strong presynaptic component.

The team has engaged into a translational project targeting aberrantly expressed KARs in temporal lobe epilepsy, in collaboration with Valérie Crépel (Inserm, Marseille). Christophe Mulle is one of the scientific founders of Corlieve Therapeutics (www.corlieve.com), a biotech company which aims at finding new therapies to cure intractable temporal lobe epilepsy. The methodology includes work on acute and organotypic human hippocampal and cortical slices from patients with intractable TLE.

 

Research Projects

Presynaptic plasticity in hippocampal circuits

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Operation and plasticity of CA3 circuits in the context of memory encoding and brain states

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Synaptic dysfunction in relation to Alzheimer’s disease (AD)

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Aberrant KARs in temporal lobe epilepsy (TLE)

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Expertise

  • Electrophysiology of Synaptic Circuits of Memory
  • Synaptic biology
  • Memory
  • Hippocampus
  • Alzheimer's disease
  • Temporal lobe epilepsy
  • Hippocampus
  • Alzheimer's disease
  • ex vivo electrophysiology (patch-clamp recordings)
  • in vivo electrophysiology (patch-clamp, silicone probe recordings)
  • Confocal and two-photon cellular imaging
  • Optogenetics and chemogenetics
  • Mouse behaviour
  • News

    Presynaptic failure in Alzheimer’s disease

    Synaptic loss is the best correlate of cognitive deficits in Alzheimer’s disease (AD). Extensive experimental evidence also indicates alterations of synaptic properties at the early stages of disease progression, before synapse loss and neuronal degeneration. A majority of studies in mouse models of AD have focused on post-synaptic mechanisms, including impairment of long-term plasticity, spine structure and glutamate receptor-mediated transmission. Here we review the literature indicating that the synaptic pathology in AD includes a strong presynaptic component. We describe the evidence indicating presynaptic physiological functions of the major molecular players in AD. These include the amyloid precursor protein (APP) and the two presenilin (PS) paralogs PS1 or PS2, genetically linked to the early-onset form of AD, in addition to tau which accumulates in a pathological form in the AD brain. Three main mechanisms participating in presynaptic functions are highlighted. APP fragments bind to presynaptic receptors (e.g. nAChRs and GABAB receptors), presenilins control Ca2+ homeostasis and Ca2+-sensors, and tau regulates the localization of presynaptic molecules and synaptic vesicles. We then discuss how impairment of these presynaptic physiological functions can explain or forecast the hallmarks of synaptic impairment and associated dysfunction of neuronal circuits in AD. Beyond the physiological roles of the AD-related proteins, studies in AD brains also support preferential presynaptic alteration. This review features presynaptic failure as a strong component of pathological mechanisms in AD.


    - Progress in Neurobiology 2020 - doi:10.1016/j.pneurobio.2020.101801
    - Authors and contacts: Gaël Barthet and Christophe Mulle

    + Cf Bordeaux Neurocampus website here

    The relationship between brain state and membrane potential in CA3 pyramidal cells

    Wakefulness is comprised of distinct brain states correlated with different behaviors and stages of memory.  It is hypothesized that memory encoding and recall are more prominent during active behaviors, while memory consolidation is more prominent during rest.  The hippocampal region of the brain is involved in all these stages of memory during their respective brain states. For this brain circuit to perform these different computations at different times, it has been hypothesized that the membrane potential of individual neurons must change in a brain state-dependent manner.  We sought to test this hypothesis by recording membrane potential from individual CA3 hippocampal pyramidal cells in awake mice during active and restful behaviors.  When animals are actively moving, the hippocampal local field potential displays a 4-12 Hz oscillation known as theta. We found that, consistent with the hypothesis, CA3 pyramidal cells underwent consistent changes in membrane potential when theta was present in the local field potential.  Specifically, these cells hyperpolarized, decreased firing, and had low membrane potential variance, all of which are consistent with increased inhibition. This sustained, coherent suppression of CA3 pyramidal cells during theta likely changes the circuit dynamics within the hippocampus, contributing to a functional switch that might underlie the ability of the hippocampus to participate in memory encoding during theta.

     

     

    - Cell Reports 2020 - doi: 10.1016/j.celrep.2020.107868

    - Authors and contacts: Meryl Malezieux, Ashley L Kees and Christophe Mulle 

    + Cf Bordeaux Neurocampus website here

    Selected Publications

  • Jiang N, Cupolillo D, Grosjean N, Muller E, Deforges S, Mulle C, Amédée T
  • Impaired plasticity of intrinsic excitability in the dentate gyrus alters spike transfer in a mouse model of Alzheimer's disease Neurobiology of Disease (2021)
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  • Malezieux, M., Kees, A.L., Mulle, C
  • Theta Oscillations Coincide with Sustained Hyperpolarization in CA3 Pyramidal Cells, Underlying Decreased Firing CellReports 32, 107868. doi:10.1016/j.celrep.2020.107868). (2020)
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  • Barthet, G., Mulle, C
  • Presynaptic failure in Alzheimer's disease Prog Neurobiol 101801. doi:10.1016/j.pneurobio.2020.101801 (2020)
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  • Jordà-Siquier, T., Petrel, M., Kouskoff, V., Cordelières, F., Frykman, S., Müller, U., Mulle, C., Barthet, G.
  • APP accumulates around dense-core amyloid plaques with presynaptic proteins in Alzheimer’s disease brai BiorXiv 77, 95–55. doi:10.1101/2020.10.16.342196 (2020)
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  • Viana da Silva, S., Zhang, P., Georg Haberl, M., Labrousse, V., Grosjean, N., Blanchet, C., Frick, A., Mulle, C.
  • Hippocampal mossy fibers synapses in CA3 pyramidal cells are altered at an early stage in a mouse model of Alzheimer's disease Journal of Neuroscience 2868–18–13. doi:10.1523/JNEUROSCI.2868-18.2019 (2019)
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  • Barthet, G., Jordà-Siquier, T., Rumi-Masante, J., Bernadou, F., Müller, U., Mulle, C
  • Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity Nature Communications 1–14. doi:10.1038/s41467-018-06813-x (2018)
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  • Carta, M., Srikumar, B.N., Gorlewicz, A., Rebola, N., Mulle, C., 2018
  • Activity-dependent control of NMDA receptor subunit composition at hippocampal mossy fibre synapses J Physiol (Lond) 596, 703–716. doi:10.1113/JP275226 (2018)
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  • Zucca, S., Griguoli, M., Malezieux, M., Grosjean, N., Carta, M., Mulle, C
  • Control of Spike Transfer at Hippocampal Mossy Fiber Synapses In Vivo by GABAA and GABAB Receptor-Mediated Inhibition Journal of Neuroscience 37, 587–598. doi:10.1523/JNEUROSCI.2057-16.2016 (2017)
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  • Larsen, A.P., Fièvre, S., Frydenvang, K., Francotte, P., Pirotte, B., Kastrup, J.S., Mulle, C.
  • Identification and Structure-Function Study of Positive Allosteric Modulators of Kainate Receptors Mol Pharmacol 91, 576–585. doi:10.1124/mol.116.107599 (2017)
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  • Maingret, V., Barthet, G., Deforges, S., Jiang, N., Mulle, C., Amédée, T
  • PGE2-EP3 signaling pathway impairs hippocampal presynaptic long-term plasticity in a mouse model of Alzheimer's disease. Neurobiology of Aging 50, 13–24. doi:10.1016/j.neurobiolaging.2016.10.012 (2017)
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  • Rebola, N., Carta, M., Mulle, C., 2017
  • Operation and plasticity of hippocampal CA3 circuits: implications for memory encoding Nat Rev Neurosci 18, 209–221. doi:10.1038/nrn.2017.10 (2017)
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  • Viana da Silva, S., Haberl, M.G., Zhang, P., Bethge, P., Lemos, C., Gonçalves, N., Gorlewicz, A., Malezieux, M., Gonçalves, F.Q., Grosjean, N., Blanchet, C., Frick, A., Nägerl, U.V., Cunha, R.A., Mulle, C
  • Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors. Nature Communications 7, 11915 (2016)
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  • Fievre, S., Carta, M., Chamma, I., Labrousse, V., Thoumine, O., Mulle, C
  • Molecular determinants for the strictly compartmentalized expression of kainate receptors in CA3 pyramidal cells Nature Communications 7, 12738. doi:10.1038/ncomms12738 (2016)
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  • George, J., Cunha, R.A., Mulle, C., Amédée, T
  • Microglia-derived purines modulate mossy fibre synaptic transmission and plasticity through P2X 4and A 1receptors European Journal of Neuroscience 43, 1366–1378. doi:10.1111/ejn.13191 (2016)
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    Members

    « Researcher »

    AMEDEE Thierry Researcher thierry.amedee@u-bordeaux.fr +33533514757
    CARTA Mario Researcher mario.carta@u-bordeaux.fr +33533514759
    MULLE Christophe Researcher christophe.mulle@u-bordeaux.fr +33533514716

    « Technical Staff »

    DEFORGES Severine Technical staff severine.deforges@u-bordeaux.fr +33533514780
    ERHARDT Anaël Technical staff anael.erhardt@etu.u-bordeaux.fr +33533514780
    GAUTRON Justine Technical staff justine.gautron@u-bordeaux.fr +33533514700
    GROSJEAN Noelle Technical staff noelle.grosjean@u-bordeaux.fr +33533514780
    LETENEUR Cindie Technical staff cindie.leteneur@u-bordeaux.fr +33533514780

    « Postdoc »

    KEES Ashley Postdoc ashley.kees@u-bordeaux.fr +33533514769
    VIOTTI Julio Postdoc julio.viotti@u-bordeaux.fr +33533514700

    « PhD student »

    LECOMTE Simon PhD student simon.lecomte@u-bordeaux.fr +33533514700
    MARNEFFE Catherine PhD student catherine.marneffe@u-bordeaux.fr +33533514700
    MOREIRA DE SA Ana PhD student ana.moreira-de-sa@u-bordeaux.fr +33533514769