Stress at the synapse: the synaptic action of acute behavioural stress and the protective effect of psychiatric drugs
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Data di Pubblicazione:
2011
Citazione:
Stress at the synapse: the synaptic action of acute behavioural stress and the protective effect of psychiatric drugs / G. Treccani, L. Musazzi, M. Milanese, P. Farisello, A. Mallei, C. Perego, G. Racagni, F. Benfenati, G. Bonanno, M. Popoli. ((Intervento presentato al convegno ECNP Workshop on Neuropsychopharmacology for Young Scientists in Europe tenutosi a Nice nel 2011.
Abstract:
Purpose of the study: Recent neuroimaging and
histopathological studies on psychiatric patients have
shown morphometrical and functional modifications in
brain areas with glutamate predominance. There are many
evidences that repeated exposure to different stressful
events represents a risk factor for neuropsychiatric
diseases. Preclinical studies showed that the exposure of
rodents to stress produces many concomitans observed
in human pathology. Indeed, in rats stress induces
morphometrical alterations in brain areas probably due
to neuronal atrophy and associated with hyperactivation
of excitatory amino acid transmission [1].
Aim of this work was to study the effect of acute stress
on glutamate release, to analyze the mechanisms whereby
stress modifies glutamate release and to understand if these
changes are dampened by chronic antidepressants.
Methods: Rats were chronically (2 weeks) treated with
vehicle or drugs employed for therapy of mood/anxiety
disorders and then subjected to a standard Footshock
(FS)-stress protocol [2]. Immediately after FS-stress,
prefrontal/frontal cortex (P/FC) was dissected and synaptosomes
were purified on Percoll gradients; glutamate release
was measured [3]. SNARE complexes were measured in
un-boiled samples of synaptic membranes by SDS-PAGE
and Western blot. Electrophysiological experiments were
performed on acute P/FC slices [3]. Changes in vesicles
mobilization were measured by Total Internal Reflection
Fluorescence Microscopy (TIRFM).
Results: Acute FS-stress induced a marked increase
of circulating corticosterone (CORT) in all stressed rats
(vehicle- and antidepressant (AD)-treated) and a rapid (non
genomic) increase of glutamate release from synaptosomes
of P/FC via selective activation of glucocorticoid receptor.
The increase of glutamate release was prevented by chronic
AD treatments [3]. On the molecular level, FS-stress
induced a rapid accumulation of SNARE complexes in
presynaptic membranes of rats pre-treated or not with
ADs. Patch-clamp recordings on P/FC pyramidal neurons
revealed that FS-stress induced changes in paired-pulse
facilitation (PPF) and its Ca2+-dependence, consistent with
an increase in glutamate release. Chronic desipramine
(DMI) completely prevented this effect [3].
Because the number of SNARE complexes per vesicle
is fixed, the accumulation induced by stress suggests
that FS-stress may increase the size of the readily
releasable pool (RRP) of vesicles (docked vesicles).
Therefore we measured the release of glutamate from
P/FC synaptosomes of control and FS-stressed rats evoked
by sucrose (250–500 mM), which mobilizes the RRP. In
line with SNARE complex accumulation, RRP size was
markedly increased in P/FC synaptosomes from stressed
rats (vehicle and ADs-treated).
Furthermore, we investigated the effects of stress on
synaptic vesicle kinetics with TIRFM. Since the effects
of CORT on glutamate release and SNARE complex
accumulation seem to be non genomic, we incubated
synaptosomes in vitro with CORT and we visualized
with TIRFM the changes induced by CORT and in vitro
depolarization on vesicle mobilization.
Conclusions: Overall, the combined results of this study
give more insight into the basic mechanisms whereby
behavioural stress affects excitatory transmission in the
forebrain and show a novel effect of ADs that could be
related to their therapeutic action.
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
G. Treccani, L. Musazzi, M. Milanese, P. Farisello, A. Mallei, C. Perego, G. Racagni, F. Benfenati, G. Bonanno, M. Popoli
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