Education and Experiences

1992-1996
B.Sc. Honors in Molecular Biology, University of Edinburgh, UK

1996-2000
Ph.D. Wellcome Trust 4-year, Ph.D. Programme in Neuroscience, University College London, UK

2001-2005
Post-Doctoral Fellow in Robert Malenka´s laboratory, Dept of Psychiatry and Behavioral Sciences, Stanford University, USA

2005-
Group Leader, European Brain Research Institute, Rome, Italy

Publications

Marie H and Nolan M Virus-based technologies for investigating function and pathology of the nervous system. Front. Cell. Neurosci. 2010, 3(16): 1-2

Marchetti C., Tafi E., Middei S., Rubinacci M., Restivo L., Ammassari-Teule M., and Marie H. Synaptic adaptations of CA1 pyramidal neurons induced by a highly effective combinational antidepressant therapy. Biological Psychiatry 2010, 67(2):146-54

Huang Y. H., Lin Y., Mu P., Lee B., Brown T., Wayman G., Marie H., Liu W., Yan Z., Sorg B.A., Schluter O., Zukin R.S., Dong Y. In vivo Cocaine Experience Generates Silent Synapses. Neuron 2009, 63:40-47

Peng Y. , He S., Marie H., Zeng S., Ma J., Tan Z., Lee S.Y., Malenka R.C., Yu X. Coordinated changes in dendritic arborization and synaptic strength during neural circuit development. Neuron 2009 Jan 15;61(1):71-84

Restivo L., Tafi E., Ammassari-Teule M., Marie H. Viral-mediated expression of a constitutively active form of CREB in hippocampal neurons increases memory. Hippocampus 2009, 19:228-234

Dong Y., Green T., Saal D., Marie H., Neve R., Nestler E.J., Malenka R.C. CREB modulates excitability of nucleus accumbens neurons. Nat Neurosci. 2006 Apr;9(4):475-7

Morishita W., Marie H. & Malenka R.C. Distinct triggering and expression mechanisms underlie LTD of AMPA and NMDA synaptic responses. Nat. Neurosci. 2005 Aug, 8(8): 1043-50

Marie H., Morishita W., Calakos N. & Malenka R.C. Generation of Silent synapses by acute in vivo expression of active CaMKIV or CREB. Neuron 2005 March 3, 45(5):741-52

Marie H., Pratt S.J., Betson M., Epple H., Kittler J.T., Meek L., Moss S.J., Troyanovsky S., Attwell D., Longmore G.D.& Braga V.M. The LIM protein Ajuba is recruited to cadherin-dependent cell junctions through an association with alpha Catenin. J. Biol. Chem. 2003 Jan 10;278(2):1220-1228

Marie H., Billups D., Bedford F.K., Dumoulin A., Goyal R.K., Longmore G.D., Moss S.J. & Attwell D. The amino terminus of the glial glutamate transporter GLT-1 interacts with the LIM protein Ajuba. Mol. Cell. Neurosci. 2002 Feb;19(2):152-164

Hamann M., Rossi D.J., Marie H. & Attwell D. Knocking out the glial glutamate transporter GLT-1 reduces glutamate uptake but does not affect hippocampal glutamate dynamics in early simulated ischaemia. Eur. J. Neurosci. 2002 Jan;15(2):308-314

Parkinson D.B., Dong Z., Bunting H., Whitfield J., Meier C., Marie H., Mirsky R. & Jessen K.R. Transforming growth factor beta (TGFbeta) mediates Schwann cell death in vitro and in vivo: examination of c-Jun activation, interactions with survival signals, and the relationship of TGFbeta mediated death to Schwann cell differentiation. J. Neurosci. 2001 Nov 1;21(21):8572-8585.

Kanungo J., Pratt S.J., Marie H. & Longmore G.D. Ajuba, a cytosolic LIM protein, shuttles into the nucleus and affects embryonal cell proliferation and fate decisions. Mol. Biol. Cell. 2000 Oct; 11(10):3299-3313

Marie H. & Attwell D. C-terminal interactions modulate the affinity of GLAST glutamate transporters in salamander retinal glial cells. J. Physiol. 1999 Oct 15;520 Pt 2:393-7

Research Projects

1) Funding agency: NARSAD Young Investigator Award (USA)

Title: Effects of chronic anti-depressant treatment on hippocampal glutamatergic transmission and neuronal excitability

Abstract: Depression is a major psychiatric illness affecting millions of people worldwide. Although anti-depressants have been used for over 50 years to treat patients, little is known about their mechanism of action. Classical antidepressants mediate their acute action by regulating brain levels of  the neuromodulators serotonin and norepinephrine. However, this acute mechanism of action is not consistent with the time course required for the therapeutic effects of these drugs, which requires weeks to months.  This led to the hypothesis that long-term antidepressant-induced adaptations of neuronal function are required for their therapeutic effects. Much work has been done to figure out the mechanisms implicated in these long-term changes, but definitive answers are still lacking.  In this proposal, we put forth a hypothesis that aims at elucidating the long-term effects of chronic antidepressant treatment on neuronal function.  Chronic, but not acute, treatment with virtually all major classes of antidepressants increases levels of expression and activation of the transcription factor CREB in the hippocampus, a brain structure implicated in depression.  Our previous studies show that if we artificially express an activated form of CREB in neurons of the hippocampus, this leads to formation of new synapses with specific properties (i.e. an increase in the number of one type of glutamatergic receptors) and increases the excitability of neurons.  These two modifications have important consequences on how neurons will contribute to brain function.   We therefore hypothesize that chronic antidepressant treatment results in similar neuronal modifications, via activation of CREB.  We will test this hypothesis by performing a thorough analysis of the physiology of the neurons in the rat hippocampus using two highly sensitive techniques (electrophysiology and confocal microscopy).  We will compare neurons of rats that have received either 14 days of fluoxetine (prozac) or placebo treatment.  We expect to detect a change in the properties of their glutamatergic synapses and excitability.  Our results will shed light on the mechanism of action of antidepressants which ultimately leads to a reduction of depressive behavior.  Once we better elucidate this mechanism, we will be one step closer to understanding the neurobiology of depression and to design more specific and targeted therapies.


2) Funding agency: Alzheimer Association New Investigator Grant (USA)

Title: Does NGF Deprivation Lead to Glutamatergic-GABAergic Network Imbalance?

Abstract: Major hallmarks of Alzheimer´s Disesase (AD) are: 1) the progressive appearance of plaques of a protein called beta-amyloid peptide (Abeta) and tangles of a protein called Tau in brain areas involved in memory, such as the hippocampus 2) death of specific neurons (called BFCN) projecting to these areas and that release the neurotransmitter acetylcholine 3) degeneration of transmission between synapses 4) debilitating memory impairments. The molecular origin of this multi-factorial disease is still largely unknown and no preventive or restorative therapies are available.  Several hypotheses were put forward to explain the various symptoms observed in AD.
The ´Abeta synaptic hypothesis´ states that early cognitive deficits in AD are due to Abeta-induced de-regulation of neuronal network balance between excitation and inhibition in the hippocampus. The molecular mechanism responsible for these alterations is still unclear.  Specific binding of Abeta to a nicotinic acetylcholine receptor (called a7nAChR) is a likely trigger for these modifications. Normal activation of a7nAChRs modulates both excitation and inhibition of neurons in the hippocampus. De-regulation of a7nAChR activity by Abeta binding could thus influence this balance.   Several reports show that a7nAChR activity is down-regulated in AD patients, mostly likely due to the loss of the BFCN.  Their loss is explained by another hypothesis.
The integrity of BFCN depends on a protein called nerve growth factor (NGF).  The ´cholinergic hypothesis´ suggests that de-regulation of NGF availability leads to both the loss of BFCN and Abeta accumulation resulting in the memory impairments observed in AD. To test this hypothesis, a mouse transgenic model, the AD11 anti-NGF mouse, was generated where NGF availability is reduced in adulthood.  These mice show a disease which resembles AD, including loss of BFCN, Abeta plaques and Tau tangles, and memory impairments. Features of the ´Abeta synaptic´ hypothesis were not tested in this model.  
In this grant, we propose experiments to unite the ´cholinergic´ and ´Abeta synaptic´ hypotheses.    Using AD11 mice, we will assess if NGF deprivation is sufficient to lead to excitatory and inhibitory imbalance through de-regulation of a7nAChR activity. We have preliminary data supporting this hypothesis. In Aim 1, we will investigate the hippocampal neuronal deficits pertinent to the Abeta hypothesis.  In Aim 2, we propose experiments to determine the origin of the defects in neuronal inhibition observed in AD mouse transgenic models.   In aim 3, we will assess the therapeutic potential of increasing normal a7nAChRs signaling.  The outcomes of this study should be two-fold: 1) we will provide new insights in the molecular mechanisms of AD pathology by linking two major hypotheses 2) we will give new important information for the development of new therapeutic tools for the fight against AD.


3) Funding Agency: Compagnia di San Paolo  (IT)

Title: Molecular Mechanisms of Memory: Identification and Modeling

Abstract: (i) Understanding how memory is formed is an essential question in Neuroscience and is necessary to treat memory disorders, like Alzheimer´s disease. Biological assays are
used to identify the molecular mechanisms responsible for memory formation, while computer-simulated models of neural networks are created to investigate how
hippocampal networks encode memory. Few studies investigated, however, how learning-induced neuronal molecular alterations identified by biologists influence these
computer-simulated networks, due to the lack of scientific interaction between these two types of investigations. (ii) We therefore created a consortium of biologists,
biophysicians and mathematicians to bridge these two disciplines and begin to fill this gap. We will combine our knowledge to create more realistic computer CA1 neuron
models. Also, we will identify how hippocampal activation of CREB, a transcription factor highly implicated in memory, results in better memory formation as previously
reported by the biologists. (iii) To accurately model CREB-dependent neuronal alterations that lead to better memory formation, we propose additional biological
experiments identifying how CREB modulates afterhyperpolarization and GABAergic transmission. Also, we will create new highly realistic BAM neural networks to
evaluate how CREB-dependent alterations affect the critical capacity of these networks. (iv) The outcome of this research will be three-fold: 1) we will provide new and more
realistic models of CA1 pyramidal neurons and complex BAM networks 2) we will identify new neuronal alterations resulting from CREB-dependent transcription 3) we
will evaluate the influence of these and previously identified CREB-dependent neuronal adaptations on the memory critical capacity of these networks.

BOOK CHAPTERS

Marie H. & Malenka R.C. Acute in vivo expression of recombinant proteins in the rat rain using Sindbis virus. Chapter 12 of The Dynamic Synapse: Molecular Methods in Ionotropic Receptor Biology. CRC Press. (2006) In press.

Awards

2008
Alzheimer’s Association 2008 New Investigator Research Grant (NIRG) recipient (USA)

2007
National Alliance for Research on Schizophrenia & Depression (NARSAD) Young Investigator
Award, (USA)

2006-present
Member of the European Neuroscience Institute Young Investigator Network

1996
1st Class Honours in Molecular Biology, Edinburgh University 1996-2000 Wellcome Trust, Ph.D. scholarship

2001-2003
Wellcome Trust International Prize Travelling Research Fellowship

Scientific Collaborations

Prof. Brunello Tirrozzi
Dipartimento di Fisica

La Sapienza, Roma

Dr. Addolorata Marasco, Ph.D.
Dipartimento di Matematica e Applicazioni “R. Caccioppoli”,

Complesso Universitario di Monte S. Angelo,

Napoli, Italy

Dr Panayiota Poirazi
Institute of Molecular Biology and Biotechnology Foundation for Research and Technology,

Heraklion, Crete, Greece

Dr. Cecconi
Fondazione Santa Lucia,

Rome, Italy

Dr. Ammassari-Teule
Fondazione Santa Lucia/CNR Instituto di Neuroscienze

Rome, Italy

Group Members

Cristina Marchetti, Gry Houeland, Elisiana Tafi, Armando Romani, Concetta Lena, Leiron Ferrarese, Mogtaba Rostamyan, Maria-Angela Rubinacci, Marco Benevento

Cristina Marchetti, c.marchetti@ebri.it

Gry Houeland, g.houeland@ebri.it

Elisiana Tafi, Research Technician e.tafi@ebri.it

Armando Romani - Ph.D. Student a.romani@ebri.it

Mogtaba Rostamyan - Undergraduate Student

ALUMNI

Concetta Lena, Undergraduate Student

Leiron Ferrarese, Undergraduate Student

Maria-Angela Rubinacci, Undergraduate Student

Marco Benevento, Undergraduate Student