Dr. Hélène Marie

Team Name: "Molecular Mechanisms of Neuronal Plasticity in Health and Disease"

Link to team page: https://www.ipmc.cnrs.fr/cgi-bin/ipmcx.cgi

Institute: Institut de Pharmacologie Moléculaire et Cellulaire (IPMC)

Address: UMR7275, CNRS/UNS, 660 Route des Lucioles, 06250 Valbonne, France

Description of research

Marie’s team is interested in understanding how physiological and pathological conditions shape neuronal plasticity. We have an integrated approach to delineate how molecular changes translate into behavioural outcomes. We have strong expertise in in vitro electrophysiology on brain slices (field and patch clamp recordings) and in behaviour. We use viral approaches for in vivo protein expression as well as transgenic lines to alter brain molecular mechanisms.  We are also currently developing pharmacogenetic and optogenetic approaches to address our questions.  Our research focuses on 3 main axis: Alzheimer disease (AD) AD is the most frequent neurodegenerative disorder. Chronic stress is known to be a key risk factor in the development of the pathology. We therefore seek to understand how stress and dysregulation of the corticotrope axis contributes to the onset of AD-related synaptic alterations and how these modifications translate into impaired mnemonic functions. Also, neuropathologically, AD is characterized by progressive appearance of oligomers of b-amyloid peptide (Ab) and plaques. Since increased Ab load per se cannot fully account for the deficits observed in AD, we explore the functional role of other peptides produced by APP processing.

Epilepsy Epilepsy is a devastating neurological disorder, which can impair brain function. In collaboration with the team of Dr. Mantegazza (IPMC), we seek to understand how synaptic function and memory are perturbed in mouse models of this disorder. Social stress When overwhelming, stress increases the morbidity for psychiatric disorders such as major depression and inability to socially perform. These aberrant behaviours are reproduced in mice repetitively exposed to social defeat stress. This results in a persistent boost of dopamine (DA) transmission. This project aims at identifying the inputs that shape DA responsiveness in response to social stress. This may form the pathophysiological basis for major psychiatric disorders. In collaboration with computational neuroscientists, we are also interested in modelling disease-related synaptic alterations to understand how these impact the function of hippocampal neurons at the single cell level and at the network level.

Research to be done in the context of Circprot

In the context of Cirprot, we will use our expertise in analysis of synapse function and neuron excitability to test if altering levels of the trophic factor BDNF can restore neuron information processing in the context of Alzheimer’s disease. We will also provide our expertise in the analysis of rodent behavior to test how manipulating BDNF alters memory processes. In particular, we will test the therapeutic benefits of several compounds, and in particular Fingolimod, a FDA-approved compound, which is known to increase endogenous BDNF levels in the brain. We will test if this compound can rescue age-dependent neuron dysfunction and memory loss in a well known mouse model of Alzheimer’s disease. Together with other partners of Cirprot, we will investigate the molecular mechanisms underlying this rescue potential. Also, in collaboration with Dr Milgiore’s team, we will provide experimental data to model these BDNF effects on neurons and to model how different therapeutic approaches alter neurons to provide rescue of function. 

 

 

Key publications

Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, Hornburg D, Evans LDB, Moore S, Daria A, Hampel H, Müller V, Giudici C, Nuscher B, Wenninger-Weinzierl A, Kremmer E., Heneka MT, Thal DR, Giedraitis V, Lannfelt L, Müller U, Livesey FJ, Meissner F, Herms J, Konnerth A, Marie H, Haass C. (2015) ?-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature, 526(7573):443-7.  

Lanté F, Chafai M, Raymond EF, Salgueiro Pereira AR, Mouska X, Kootar S,  Barik J, Bethus I,  Marie H. (2015) Subchronic glucocorticoid receptor inhibition rescues early episodic memory and synaptic plasticity deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology. 40:1772-81.

Marcantoni A, Raymond EF, Carbone E, Marie H. (2014)  Firing properties of entorhinal cortex neurons and early alterations in an Alzheimer´s disease transgenic model.  Pflugers Arch. 466(7):1437-50  IF: 3.03

Romani A, Marchetti C, Bianchi D, Leinekugel X, Poirazi P, Migliore M, Marie H (2013) Computational modeling of the effects of amyloid-beta on release probability at hippocampal synapses.  Front.  Comp. Neurosci. 7:1. 

D’Amelio M., Cavallucci V., Middei S., Marchetti C., Pacioni S., Ferri A., Diamantini A., De Zio D., Carrara P., Battistini L., Moreno S.,  Bacci A., Ammassari-Teule M., Marie H., Cecconi F. (2011) Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s Disease.  Nat Neurosci 14:69-76.