Neurotransmission et signalisation

Co-Leaders

Denis
HERVE

Research center

IFM -Institut du Fer à Moulin
17 rue du Fer à Moulin
75005 Paris
Jean Antoine Girault

Institution

Inserm
Université Pierre et Marie Curie
ED158
Université Pierre et Marie Curie

Laboratory

UMRS 839
Site web
Contrat ANR, Brixham Foundation Prize (FRM, 2016)
 

publications

- Pelosi A, Menardy F, Popa D, Girault JA, Hervé D. Heterozygous Gnal mice are a novel animal model to study dystonia pathophysiology. J Neurosci. 2017, 37:6253-67. 


- Giralt A, Brito V, Chevy Q, Simonnet C, Otsu Y, Cifuentes-Díaz C, de Pins B, Coura R, Alberch J, Ginés S, Poncer JC, Girault JA. Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington's disease model. Nat Commun. 2017, 8:15592.

- Engmann O, Giralt A*, Gervasi N*, Marion-Poll L, Gasmi L, Filhol O, Picciotto MR, Gilligan D, Greengard P, Nairn AC, Hervé D, Girault JA. DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons. Nature Commun, 2015, Dec 7;6:10099.

- Li L*, Gervasi N*, Girault JA.  Dendritic geometry shapes neuronal cAMP signaling to the nucleus. Nature Comm, 2015, 6:6319.

- Brami-Cherrier K, Gervasi N, Arsenieva D, Walkiewicz K, Boutterin MC, Ortega A, Leonard PG, Seantier B, Gasmi L, Bouceba T, Kadaré G, Girault JA*, Arold S*.  Dimerization controls activation of kinase-dependent functions of FAK at focal adhesions. EMBO J, 2014, 33:356-7.*Equal contribution

Fields of research

Neuropharmacology / cell signaling

Research Theme

Notre objectif est de caractériser les mécanismes de signalisation intracellulaire qui sous-tendent la plasticité cérébrale responsable d’adaptations comportementales. Notre principal modèle est le striatum qui participe à l’élaboration des mouvements, à la motivation et à la formation des habitudes. Le striatum est impliqué dans diverses maladies neurologiques et psychiatriques, en particulier la maladie de Parkinson et la toxicomanie. La dopamine contrôle la fonction du striatum et la plasticité de ses circuits, contribuant ainsi à l’apprentissage par renforcement positif.

Les drogues toxicomanogènes détournent ces processus en augmentant directement la transmission dopaminergique. Des mécanismes similaires interviennent dans les mouvements anormaux induits par la L-DOPA chez les patients parkinsoniens. Nous étudions les voies de signalisation (protéines G, protéines kinases et phosphatases, et expression de gènes) activées par la dopamine, le glutamate, les endocannabinoïdes et d’autres neuromédiateurs. Nous cherchons à préciser leur rôle dans des comportements simples et à identifier les assemblées de neurones dans lesquels elles sont activées. Nous étudions aussi d’autres enzymes de signalisation comme les tyrosines kinases non récepteurs FAK et PYK2.

Lab rotation

Synaptic plasticity-induced ERK dynamics in striatal projection neurons

Chercheur responsable: 

GIRAULT Jean Antoine

Dates: 

9 July 2018 - 28 September 2018

Date limite de candidature: 

9 July 2018

Period

~ July-Sept 2018

Project

The striatum is a major entry structure of the basal ganglia. It receives a convergent excitatory glutamate input (from cortex and thalamus), controlled by dopamine (DA) released. DA receptors are segregated into distinct neuronal populations in the striatum, D1R expressing SPN and D2R SPN. In D1-SPN, the extracellular signal-regulated kinase (ERK) kinase pathway can detects combination of glutamate and dopamine release and is essential for long-lasting modifications. In addition, striatal plasticity is significantly altered in pathological conditions in which either a loss of DA innervation (Parkinson’s disease) or aberrant DA release (drug addiction and L-DOPA induced dyskinesia) occurs. 

The spatiotemporal activation of ERK pathways in D1 SPN in responses to synaptic plasticity relevant activation is unknown. To gain deeper insights ERK pathway dynamics in SPN, we will combine multiphoton microscopy with FRET biosensors, pharmacological stimulation and/or LTP induction in adult mice striatal slices. The project will start by using pharmacological stimulation like D1R and/or glutamatergic receptor agonist to activate ERK pathway. The expected results will show that co-stimulation produce a synergistic activation of ERK pathway. The next step will be to test different long-term plasticity protocols and to record using multiphoton imaging ERK dynamics in SPN. We will also use pharmacological inhibition of the ERK pathway (by U0126) to understand if specific ERK activation are involved in LTP induction or maintenance.

The mechanisms involved in the induction of striatal LTP appears to be extremely complex. We think that imaging intracellular signalling pathways will help to understand the discrepancy between various LTP protocols. And extract the central role of ERK dynamics in the long term regulation of SPNs.

Contact

Institut du Fer à Moulin  - 17, rue du Fer à Moulin 75005 PARIS- jean-antoine.girault@inserm.fr

Superviseur: 

Nicolas GERVASI