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

Corlieve Therapeutics, co-funded by Christophe Mulle acquired by the 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/

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APP accumulates with presynaptic proteins around amyloid plaques: a key feature in Alzheimer disease

In Alzheimer's disease (AD), the distribution of the amyloid precursor protein (APP) and its fragments other than amyloid beta, has not been fully characterized. Here, we investigate the distribution of APP and its fragments in human AD brain samples and in mouse models of AD in reference to its proteases, synaptic proteins, and histopathological features characteristic of the AD brain, by combining an extensive set of histological and analytical tools. We report that the prominent somatic distribution of APP observed in control patients remarkably vanishes in human AD patients to the benefit of dense accumulations of extra-somatic APP, which surround dense-core amyloid plaques enriched in APP-Nter. These features are accentuated in patients with familial forms of the disease. Importantly, APP accumulations are enriched in phosphorylated tau and presynaptic proteins whereas they are depleted of post-synaptic proteins suggesting that the extra-somatic accumulations of APP are of presynaptic origin. Ultrastructural analyses unveil that APP concentrates in autophagosomes and in multivesicular bodies together with presynaptic vesicle proteins. Altogether, alteration of APP distribution and its accumulation together with presynaptic proteins around dense-core amyloid plaques is a key histopathological feature in AD, lending support to the notion that presynaptic failure is a strong physiopathological component of AD.

APP accumulates with presynaptic proteins around amyloid plaques: a role for presynaptic mechanisms in Alzheimer’s disease?
Authors: Tomàs Jordà-Siquier, Melina Petrel, Vladimir Kouskoff, Una Smailovic, Fabrice Cordelières, Susanne Frykman, Ulrike Müller, Christophe Mulle, Gaël Barthet

Alzheimer's & Dementia, The Journal of the Alzheimer's Association - 25 January 2022 DOI: 10.1002/alz.12546

Contacts: Gaël Barthet and Christophe Mulle

+ Cf. CNRS Press release in French here
+ Cf Bordeaux Neurocampus website here

Awarded 2022 Prize for Innovation of the Académie des Sciences et Belles Lettres de Bordeaux

Valérie Crépel (INSERM) at the University of Aix-Marseille and Christophe Mulle (CNRS) at the Interdisciplinary Institute for Neuroscience at the University of Bordeaux have been awarded the 2022 Prize for Innovation of the Académie des Sciences et Belles Lettres de Bordeaux.

Valérie Crépel and Christophe Mulle are very high-level researchers interested in the physiology and pathology of the hippocampus circuits, a region of the brain located in the temporal lobes, which is the seat of memory and learning.

Their highly innovative research focuses on the therapeutic approach to the treatment of temporal lobe epilepsy. This pathology affects 1.3 million people in Europe and the United States, including 800,000 patients who are resistant to known treatments. Christophe Mulle and Valérie Crépel propose gene therapy as an alternative to surgery and its drawbacks. Their therapeutic proposal is developed within Corlieve Therapeutics: it uses microRNA technology, nucleic acids capable of acting at the level of messenger RNA to selectively reduce aberrant effects in the hippocampus of patients.

 

Selected Publications

Jordà-Siquier, T., Petrel, M., Kouskoff, V., Smailovic, U., Cordelières, F., Frykman, S., Müller, U., Mulle, C., Barthet, G.

APP accumulates with presynaptic proteins around amyloid plaques: A role for presynaptic mechanisms in Alzheimer's disease? Alzheimers Dementia (2022)
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Barthet, G., Moreira-de-Sa, A., Zhang, P., Castanheira, J., Gorlewicz, A., Mulle, C

Presenilin and APP regulate synaptic kainate receptors bioRxiv (2022)
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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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• 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)
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Mulle, C., Crépel, V.

Regulation and dysregulation of neuronal circuits by KARs. Neuropharmacology (2021)
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• 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)
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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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Kees AL, Marneffe C, Mulle C.

Lighting up pre-synaptic potentiation: An Editorial for "SynaptoPAC, an optogenetic tool for induction of presynaptic plasticity" J Neurochem. (2020)
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Robert BJA, Moreau MM, Dos Santos Carvalho S, Barthet G, Racca C, Bhouri M, Quiedeville A, Garret M, Atchama B, Al Abed AS, Guette C, Henderson DJ, Desmedt A, Mulle C, Marighetto A, Montcouquiol M, Sans N

Vangl2 in the Dentate Network Modulates Pattern Separation and Pattern Completion. Cell Rep. (2020)
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Gorlewicz A, Krawczyk K, Szczepankiewicz AA, Trzaskoma P, Mulle C, Wilczynski GM

Colocalization Colormap -an ImageJ Plugin for the Quantification and Visualization of Colocalized Signals. Neuroinformatics (2020)
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Pigoni M, Hsia HE, Hartmann J, Rudan Njavro J, Shmueli MD, Müller SA, Güner G, Tüshaus J, Kuhn PH, Kumar R, Gao P, Tran ML, Ramazanov B, Blank B, Hipgrave Ederveen AL, Von Blume J, Mulle C, Gunnersen JM, Wuhrer M, Rammes G, Busche MA, Koeglsperger T, Lichtenthaler SF

Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3. EMBO J (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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Abarkan M, Gaitan J, Lebreton F, Perrier R, Jaffredo M, Mulle C, Magnan C, Raoux M, Lang J

The glutamate receptor GluK2 contributes to the regulation of glucose homeostasis and its deterioration during aging. Mol Metab. (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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