France PhD Grant 2009 2010

Title: Intracellular signaling cascades involved
in the integration of neuromodulatory signals in the
striatum / nucleus accumbens.

Project:
As a majority of neuropsychiatric diseases
affect neuromodulatory systems, it becomes
increasingly important to gain a better
understanding of the cellular processes involved in signal
integration. For example, dopamine plays a
key role in controlling the output of basal ganglia
such as complex motor sequences (dorsal
striatum) or behavioral orientation (“motivation”,
ventral striatum).

Imbalances in the
dopaminergic system indeed result in debilitating conditions
such as Parkinson disease, addiction,
psychosis... In the striatum, medium spiny neurons (MSN)
express either dopamine D1 or D2 receptors
which are coupled in an opposite way to the cAMP/
PKA cascade. These neurons also express
proteins isoforms involved in the cAMP/PKA cascade
which are rare or absent in any other
brain region, such as DARPP-32, Gαolf,
type V adenylyl
cyclase, type 10 phosphodiesterase… This
signaling cascade is therefore expected to perform
differently in the striatum than in other
region of the brain.
The very recent development of FRET
biosensors now allow a direct assessment of the cAMP/
PKA cascade in living neurons. There are
indicators for various steps of the cascade (cAMP
concentration, PKA activity and CREB
phosphorylation level) and we routinely record D1
responses in medium spiny neurons in
specific cellular domains (cytosol, nucleus, dendrites). In
addition, we are developing a unique
method to record this signal in the striatum at the cellular
level in the living animal. Our preliminary
results demonstrated a more complex regulation of
the PKA signal in MSN as compared to our
former results obtained in the cortex, which must
now be explained at the molecular level. Our
project is to study the cAMP/PKA signalisation in
different cellular domains in
physiological and pathological situations in animal models of
Parkinson disease and drug addiction.
We thus use very innovative methodologies
to combine mechanistic studies performed ex vivo
with cellular recordings performed in vivo, in an attempt to bridge the gap between
cellular and
integrated physiology.

References
Gervasi, Hepp, Tricoire, Zhang, Lambolez,
Paupardin-Tritsch and Vincent, 2007, "Dynamics of
PKA Signaling at the Membrane, in the
Cytosol and in the Nucleus of Neurons in Mouse Brain
Slices" J. Neurosci. 27 p2744-50.
Vincent, Maskos, Charvet, Bourgeais,
Stoppini, Leresche, Changeux, Lambert, Meda and
Paupardin-Tritsch, 2006, "Live
imaging of neural structure and function by fibred fluorescence
microscopy." EMBO Rep. 7 p1154-61.
Vincent, Gervasi and Zhang, 2008,
"Real-time monitoring of cyclic nucleotide signaling in
neurons using genetically encoded FRET
probes." Brain
Cell Biol 36
p3-17.
Contact:
Pierre VINCENT; Equipe Intégration Cellulaire des Signaux
Neuromodulateurs
Neurobiologie des Processus Adaptatifs UMR7102 CNRS UPMC, Paris,
France.
phone: 33 (0)1 44 27 25 88; e-mail: pierre.vincent@upmc.fr
http://npa.snv.jussieu.fr/eq/theme_eq.php?eq=icsn〈=en

PhD grant from CNRS: https://www2.cnrs.fr/DRH/doctorants-09/