Research Projects

Presynaptic plasticity in hippocampal circuits

MORE

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

MORE

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

MORE

Aberrant KARs in temporal lobe epilepsy (TLE)

MORE

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

Corlieve Therapeutics rachetée par la biotech uniQure:

Corlieve Therapeutics co-funded by Christophe Mulle and Valérie Crépel (Inserm Marseille) acquired by the biotech uniQure
The acquisition of Corlieve Therapeutics by uniQure amounts to 250 million euros, of which the first initial settlement of 46.3 million euros finalizes the transaction.
The story of deeptech Corlieve Therapeutics is the meeting between leading researchers (Christophe Mulle and Valérie Crépel), an early investor and a high level entrepreneur.
The union of two transfer offices has made it possible to promote and transfer technology that is beneficial for research and project leaders.
9 years, the time necessary for the research to lead to a successful transfer to a biotech company.

https://www.bordeaux-neurocampus.fr/en/uniqure-to-acquire-corlieve-therapeutics/

 

MORE

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)
MORE

• Haytural, H., Jordà-Siquier, T., Winblad, B., Mulle, C., Tjernberg, L.O., Granholm, A.-C., Frykman, S., Barthet, G

Distinctive alteration of presynaptic proteins in the outer molecular layer of the dentate gyrus in Alzheimer's disease Brain Communications (2021)
MORE

Mulle, C., Crépel, V.

Regulation and dysregulation of neuronal circuits by KARs. Neuropharmacology (2021)
MORE

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 brain Alzheimer's and Dementia (2021)
MORE

• Adam Gorlewicz, Gael Barthet, Stefano Zucca, Peggy Vincent, Marilena Griguoli, Noëlle Grosjean, Grzegorz Wilczynski, Christophe Mulle

The deletion of GluK2 alters cholinergic control of neuronal excitability Cerebral Cortex (2021)
MORE

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)
MORE

Barthet, G., Mulle, C

Presynaptic failure in Alzheimer's disease Prog Neurobiol 101801. doi:10.1016/j.pneurobio.2020.101801 (2020)
MORE

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)
MORE

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)
MORE

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)
MORE

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)
MORE

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)
MORE

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)
MORE

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)
MORE

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)
MORE

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)
MORE

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)
MORE

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)
MORE