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 . 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 . 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 . 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  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.  Shakesby AC, Anwyl R, Rowan MJ, 2002, Overcoming the effects of stress on synaptic plasticity in the intact hippocampus: rapid actions of serotonergic and antidepressant agents. J Neurosci 22, 3638–3644.  Overstreet DH, Friedman E, Math AA, et al., 2005, The Flinders Sensitive Line rat: a selectively bred putative animal model of depression. Neurosci Biobehav Rev 29, 739–759.
|Titolo:||Functional and molecular correlates of synaptic plasticity in a gene - environment combination rat model of depression|
|Autori interni:||POPOLI, MAURIZIO (Ultimo)|
MUSAZZI, LAURA (Primo)
BARBIERO, VALENTINA (Secondo)
RACAGNI, GIORGIO ANGELO
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2007|
|Digital Object Identifier (DOI):||10.1016/S0924-977X(07)70028-7|
|Appare nelle tipologie:||01 - Articolo su periodico|
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