MODELING GLUTAMATERGIC SYNAPSES: INSIGHTS INTO MECHANISMS REGULATING SYNAPTIC EFFICACY
MODELING GLUTAMATERGIC SYNAPSES: INSIGHTS INTO MECHANISMS REGULATING SYNAPTIC EFFICACY JEAN-MARIE C. BOUTEILLER, MICHEL BAUDRY, SUSHMITA L. ALLAM, RENAUD J. GREGET, SERGE BISCHOFF and THEODORE W. BERGER BME Department, University of Southern California Los Angeles, CA 90089, USA and Rhenovia Pharma, Mulhouse, France
Theodore Berger, Michel Baudry and Jean-Marie Bouteiller, from left
Two USC faculty members and the French drug discovery company
Rhenovia Pharma have been awarded a biomedical research partnership by
the National Institutes of Health to study the amino acid behind
Michel Baudry, a professor in the USC College department of
biological sciences and principal investigator of the project, along
with Theodore Berger of the USC Viterbi School’s department of
biomedical engineering, will work with Serge Bischoff, the CEO of
The object of their research is a single neurotransmitter, the amino acid L-glutamate, which regulates biological systems.
But even though scientists have known for decades that glutamate
functions as a neurotransmitter and have found that numerous diseases,
including possibly schizophrenia, are linked to “glutamatergic”
transmission malfunctions, no drugs to treat these malfunctions yet
exist, despite intense efforts.
The researchers on this interdisciplinary study hope to learn enough
to change this situation by using large-scale computer modeling to
predict synergistic interactions within glutamate systems that might be
targets for new drugs.
Successful funding of this proposal is notable for the unique
structure of the research team and for the novelty of the scientific
approach, Baudry said. The grant will support joint research by the
three partners for four years, with the total amount of funding
reaching $2.3 million.
Berger said the research effort is to develop a new technology of
mathematical modeling, as well as computer simulation tools, to
systematically explore molecular processes underlying glutamatergic
“This approach will not only provide an intimate understanding of
the contribution of specific molecular events to synaptic plasticity
and ultimately overall systems function, but it also will facilitate
the design of better and safer therapeutic strategies for learning and
memory impairments,” Berger said.
According to Baudry. “The problem with glutamate in terms of
pharmaceuticals is that this molecule is absolutely ubiquitous
throughout the body,” he said. “What is therapeutic in one area can be
toxic in another. The trick is to find a way to home in on the specific
neural cells you want to affect, without disturbing the others.”
One target the group will focus on is the hippocampal region,
critical to learning and memory. Additionally, several neurological
conditions, such as schizophrenia, are believed to be related to
regulatory disruption of the glutamatergic system, Berger said.
The research to be conducted by the USC and French research teams is
centered on a detailed model of glutamatergic synaptic transmission,
called EONS, first developed by Jean-Marie Bouteiller, a research
assistant professor working in Berger’s laboratory.
Bouteiller and Berger’s research on EONS was, and still is,
supported by the USC Biomedical Simulations Resource, a center in the
biomedical engineering department of the USC Viterbi School dedicated
to the development of new methods for mathematically modeling
Thus, said Baudry, the collaboration was a “natural,” and represents
an example of the new emphasis on translational science, realized
through collaborations that extend to, and include, industry, including
researchers at USC, the University Louis Pasteur in Strasbourg and
engineering and scientific staff at Rhenovia Pharma.
Coordination and management are accomplished through weekly
conference calls, e-mail and travel to and from Mulhouse, where the
group recently held its first meeting.
RHENOMS - PFG-1™: Bio simulation
systems consist of multitudes of interactions between complex mechanisms;
pathologies often reflect the complexity of these interactions...
discovery (DD) strategy for
and other brain diseases
DIVERSITY FOR BETTER DRUGS
medical needs, especially for Alzheimer's disease, are mostly due to the fact
that all brain pathologies are extremely complex, multifactorial and dynamic.
Furthermore, brain diseases are most probably of multiple origins and involve
separate, physiological mechanisms, multiple pathways and neuronal/glial
interactions. They might also affect dynamic features such as
feedback/feed-forward regulations and cross-talk between extracellular and
intracellular mechanisms. For these reasons, the conventional Drug Discovery
(DD) approach followed by most pharmaceutical companies might not be sufficient
to address the multiple facets of these diseases. In particular, the
single-target, single-mechanism approach so suited for high-throughput
screening may not result in optimal identification of candidate therapeutics.
INNOVATIVE APPROACH: SIMULATION PLATFORM FOR COGNITION
international team is developing an alternative DD strategy which takes into
account most of these considerations:
Complexity, by developing a unique technology which allows testing the
pharmacological properties of a molecule based on its actions on physiological
functions by integrating its dynamic interactions with the whole system;
facets of the diseases, by searching for combinations of drugs that act
simultaneously on multiple targets, and by identifying optimal combinations of
two or more drug principles providing synergistic pharmacological effects.
aim, we utilize a hybrid approach combining computer-assisted simulation of the
molecular events taking place at excitatory glutamatergic synapses embedded
into small neuronal networks and experimental validation.