Functional and molecular correlates of synaptic plasticity in a gene - environment combination rat model of depression
Articolo
Data di Pubblicazione:
2007
Citazione:
Functional and molecular correlates of synaptic plasticity in a gene - environment combination rat model of depression / L. Musazzi, V.S. Barbiero, A. Mallei, A. Mathè, A. El Khoury, S.H. Gruber, G. Racagni, B.K. Ryan, M.J. Rowan, M. Popoli. - In: EUROPEAN NEUROPSYCHOPHARMACOLOGY. - ISSN 0924-977X. - 17:Suppl. 1(2007), pp. S24-S24. ((Intervento presentato al convegno ECNP Workshop on Neuropsychopharmacology for Young Scientists in Europe tenutosi a Nizza nel 2007 [10.1016/S0924-977X(07)70028-7].
Abstract:
Purpose and Methods: Genetic studies found no evidence
of classic Mendelian inheritance for human depression,
while stress factors, such as early-life adverse events, have
been shown to interact with a variable background of
genetic vulnerability. Indeed, the experience of stressful
events in childhood was found to increase the risk for
the development of mood disorders in adult life [1].
Moreover, stress can profoundly affect cognitive functions
and alter hippocampal synaptic plasticity. Antidepressants
have been shown to induce various effects beyond
neurotransmitters receptors, such as adaptive changes in
gene expression and neuroplasticity. These drugs were also
shown to affect long-term potentiation (LTP), a synaptic
mechanism underlying learning and memory [2]. We
employed an innovative experimental design, attempting
at reproducing the combination of environmental adverse
events and genetic susceptibility. We used the Flinders
Sensitive Line (FSL) rats, a well-validated model of
depression carrying genetic vulnerability associated to
distinct features of pathology [3]. To reproduce early life
stress events the FSL rats and their controls, the Flinders
Resistant Line (FRL) rats, were subjected to a standard
maternal separation protocol. Moreover, FSL and FRL
rats, with or without early-life stress, were treated with
escitalopram. LTP was induced in vivo in the hippocampus
of FSL/FRL rats by means of high frequency stimulation
(HFS) protocol. Furthermore, we purified synaptosomes
from the hippocampus of FSL/FRL (not subjected to HFS)
and analyzed protein-protein interactions pre- and postsynaptically,
as well as changes in synaptic signaling, in
order to identify molecular correlates of early-life stress
and response to escitalopram treatment.
Results and Conclusions: In vivo LTP was significantly
lower in basal FSL rats. LTP was reduced in both FRL
and FSL escitalopram-treated rats. Maternal separation did
not induce significant LTP changes; however, there was
a tendency toward increased LTP in FSL after maternal
separation. LTP was not further changed by escitalopram
in FRL maternally separated, while it was reduced,
although not significantly, in FSL maternally separated
treated with the antidepressant. Basal expression level of
NMDA-NR1 subunit in synaptosomes of FSL was lower
and early life stress upregulated NR1 levels. Interaction
between CaMKII and NMDA-NR2A/B subunit was
reduced in FSL rats compared with FRL, consistent with
a lower synaptic NMDA receptor content. Furthermore,
we found basal differences between FSL and FRL in
phosphorylation levels of CaMKII and of Synapsin-1
(CaMKII site) and in the interaction between CaMKII and
syntaxin-1. These results combined suggest a dysfunction
of glutamate neurotransmission in FSL. Finally, basal
phosphorylation levels of the stress-sensitive kinases
ERK1/2 in synaptosomes of FSL were higher and early
life stress failed to further increase kinases activation,
contrary to the results obtained in FRL. Our experimental
design superimposing early environmental adverse events
on a genetic background of vulnerability allowed for
functional and molecular studies in an animal model
more thoroughly reproducing pathology. Our results may
contribute to characterize the molecular effectors of
plasticity that mediate vulnerability to stress and response
to antidepressant action.
References
[1] Caspi A, Sugden K, Moffitt TE, et al., 2003,
Influence of life stress on depression: moderation by a
polymorphism in the 5-HTT gene. Science 301, 386–
389.
[2] Shakesby AC, Anwyl R, Rowan MJ, 2002, Overcoming
the effects of stress on synaptic plasticity in the
intact hippocampus: rapid actions of serotonergic and
antidepress
Tipologia IRIS:
01 - Articolo su periodico
Elenco autori:
L. Musazzi, V.S. Barbiero, A. Mallei, A. Mathè, A. El Khoury, S.H. Gruber, G. Racagni, B.K. Ryan, M.J. Rowan, M. Popoli
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