Supervisory authorities


Presentation of the institute



Synaptic Circuits of Memory

Team leader: Christophe Mulle

Christophe Mulle is a cellular neurobiologist with expertise in cellular electrophysiology of synaptic transmission and plasticity, receptor cell biology, generation of transgenic mice.
Since 1995, he has established a CNRS laboratory in Bordeaux which is interested in the cellular biology and pathophysiology of glutamatergic synaptic transmission and plasticity.
Christophe Mulle has been trained in the laboratory of Jean-Pierre Changeux at the Institut Pasteur, as a cellular electrophysiologist. He was among the first to identify and characterize functional nicotinic receptors in the mammalian brain. He also spent two years in the laboratory of Mircea Steriade and Martin Deschênes where he provided evidence for the central role of the nucleus reticularis thalami in the generation of thalamic spindle waves, by performing intracellular recordings in vivo.
During a two-year period at the Salk Institute in San Diego, he trained in molecular biology techniques and generated knock-out mice for kainate receptor subunits, which have proved to be instrumental for understanding the function of these elusive glutamate receptors. In addition he has provided the first insights into the molecular events that govern polarized trafficking of kainate receptors.

Contact: Christophe Mulle, tel. +33 (0)5 33 51 47 16

Project Summary

The research carried out in the group ambitions to link cell biological mechanisms of protein trafficking to synaptic function and dysfunction.
Great efforts are made to implement these questions at an integrated ex vivo or in vivo level in the mouse.

The general long–term objectives of the project aim at answering the following questions:

- What are the molecular mechanisms governing synapse specification and subcellular segregation of glutamate receptors in a given neuron?
- How does synaptic morphology impact on synaptic function at individual synapses, especially during developmental maturation?
- How do presynaptic and postsynaptic parameters integrate to determine proper network function?
- How does synaptic plasticity modify information transfer, network activity and contribute to memory?
- How does synaptic dysfunction cause cognitive disorders, such as mental retardation and Alzheimer’s disease?

Our projects revolve around two main scientific centers of interest: 1) kainate receptors (KARs) and their involvement in brain function and dysfunction and 2) CA3 pyramidal cells which display clearly segregated glutamatergic inputs and are a major stage of hippocampal information processing in learning and memory processes.
The studies rely on a combination of approaches ranging from molecular biology and gene-transfer in the brain to synaptic electrophysiology and live imaging. We have invested considerable effort in the development of gene-transfer methods in slices and in vivo:
(i) biolistic transfection of hippocampal slices for molecular rescue experiments, and
(ii) production of lentiviruses and AAV constructs, and in vivo sterotaxic infection in pups and young mice. These methods are fundamental for a number of projects proposed. Confocal imaging setups coupled to electrophysiology serve to couple electrophysiology to glutamate uncaging, Ca2+ imaging and morphological analysis, and Image acquisition and analysis is made possible thanks to the central imaging facility (BIC).

We are currently developing the use of electrophysiological recordings in vivo (patch-clamp and extracellular recordings), that will be ultimately combined with optogenetic stimulation of neurons.

Keys Publications

1. Rebola N, Carta M, Lanore F, Blanchet C, Mulle C (2011) NMDA receptor-dependent metaplasticity at hippocampal mossy fiber synapses. Nat Neurosci 14:691-693.

2. Lanore F, Labrousse VF, Szabo Z, Normand E, Blanchet C, Mulle C (2012) Deficits in morphofunctional maturation of hippocampal mossy fiber synapses in a mouse model of intellectual disability. Journal of Neuroscience 32, 17882–17893.

3. Veran J, Kumar J, Pinheiro PS, Athané A, Mayer ML, *Perrais D, *Mulle C (2012). Zinc Potentiates GluK3 Glutamate Receptor Function by Stabilizing the Ligand Binding Domain Dimer Interface. Neuron 76, 565–578. *Equal contribution

4. Carta M, Opazo P, Veran J, Athané A, Choquet D, *Coussen F, *Mulle C (2013). CaMKII-dependent phosphorylation of GluK5 mediates plasticity of kainate receptors. The EMBO Journal 32, 496–510. *Equal contribution

5. Carta M, Lanore F, Rebola N, Szabo Z, Viana Da Silva S, Lourenço J, Verraes A, Nadler A, Schultz C, Blanchet C, Mulle C (2014) Membrane lipids tune synaptic transmission by direct modulation of presynaptic potassium channels. Neuron , 81:787–799.

6. Vergnano A, Rebola N, Savtchenko L, Pinheiro P, Kieffer B, Rusakov D, *Mulle C and *Paoletti P (2014). Zinc dynamics and action at excitatory synapses. Neuron 82, 1101–1114. *Equal contribution

7. Viana da Silva S, Haberl MG, Zhang P, Bethge P, Lemos C, Gonçalves N, Gorlewicz A, Malezieux M, Gonçalves FQ, Grosjean N, Blanchet C, Frick A, Nägerl UV, Cunha RA, Mulle C (2016). Early synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors. Nature Communications 7, 11915.

8. Fievre S, Carta M, Chamma I, Labrousse V, Thoumine O, Mulle C (2016). Molecular determinants for the strictly compartmentalized expression of kainate receptors in CA3 pyramidal cells. Nature Communications 7, 12738.

9. Zucca S, Griguoli M, Malezieux M, Grosjean N, Carta M, Mulle C (2017). Control of Spike Transfer at Hippocampal Mossy Fiber Synapses In Vivo by GABAA and GABAB Receptor-Mediated Inhibition. J Neurosci 37, 587–598.

10. Rebola N, Carta M, Mulle C (2017). Operation and plasticity of hippocampal CA3 circuits: implications for memory encoding. Nat Rev Neurosci 18, 209–221.

11. Barthet, G., Jordà-Siquier, T., Rumi-Masante, J., Bernadou, F., Müller, U., Mulle, C., (2018). Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity. Nature Communications 1–14. doi:10.1038/s41467-018-06813-x

12. Viana da Silva, S., Zhang, P., Georg Haberl, M., Labrousse, V., Grosjean, N., Blanchet, C., Frick, A., Mulle, C. (2019). 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