Brain-Derived Neurotrophic Factor (BDNF) is a memberof the neurotrophin family which includes a groupof molecules important for the development and themaintenance of the nervous system. Since BDNF is highlyexpressed in the hippocampus, the action and regulationof this neurotrophin in this area has become subject of intense study. The gene codifying for BDNF is a stressresponsivegene and alterations in its expression may beimportant in regulating some of the physiological andpathophysiological effects of chronic and acute stress inthe hippocampus. Different studies show that several typesof stress reduce BDNF expression in the hippocampusof control animals [Smith et al., 1995] and these worksled to a neurotrophic hypothesis of depression [Nestleret al., 2002]. Nevertheless, the effect of stress on BDNFgene expression may differ between a "normal" and a"pathological" brain.In our study, we used transgenic mice with glucocorticoidreceptor impaired (GRi) expression created [Pepinet al., 1992], as a tool to study the neuroendocrinechanges observed in stress-related disorders, such as majordepression. This GRi mouse model is characterized bydysfunctional glucocorticoid inhibitory feedback and anexcessive activation of the hypothalamic pituitar~adrenal(HPA) axis, that can be restored by antidepressant drugs'treatment. The hypothesis was tested that a single periodof 30 minutes of restraint stress affects BDNF expressionin the hippocampus of GRi mice differently than in wildtype(WT) mice. Using RNase protection assay and insitu hybridization we had assessed the BDNF mRNAhippocampal levels, while the levels of BDNF and itsprecursor, pro-BDNF were analyzed by western blotting.Our results indicated that 30 minutes of restraintenhanced BDNF mRNA expression in the CA3 hippocampalsubregion of GRi mice; the same stress procedureinduced also a statistically significant increase of pro-BDNF level in hippocampus of GRi mice. No effectof acute stress was observed in the WT at the levelof the expression of BDNE Moreover, we evaluated theeffects of restraint on signalling pathways implicated inthe regulation of BDNF expression (mitogen-activatedprotein kinase and calcium/calmodulin-dependent kinasecascades) that converge on the phosphorylation of CREBthat we found down-regulated in the hippocampus of GRimice and up-regulated in WT mice.Our data suggest that, in the presence of psychophysiologicalstress (restraint stress), GRi mice displayaltered hippocampal regulation in BDNF gene expression.Thus, life-long central GR dysfunction may negativelyaffects neural functioning by limiting the capacity to copewith change or acute stress, which could be a predisposingor determining factor in depression. Understanding themechanisms underlying the induction of BDNF mRNAand accumulation of pro-BDNF in the hippocampus ofGRi mice, may help to clarify the molecular basis of actionof this neurotrophin and contribute to the development ofnew strategies reducing the vulnerability of neurons tostress, thus preventing neuropathological alterations in thehippocampus.
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|Data di pubblicazione:||2006|
|Titolo:||Effects of acute stress on brain-derived neurotrophic factor in the hippocampus of transgenic mouse model of depression|
|Autori:||Alboni S; Blom JMC; Corsini D; Benatti C; Capone G; Ferraguti C; Barden N; Tascedda F; Brunello N|
|Data del convegno:||16-20 September 2006|
|Nome del convegno:||The Melatonergic Approach in Depression: From Pharmacology to Clinical Evidence - Proceedings of a Satellite Symposium held on the occasion of the 19th ECNP Congress|
|Luogo del convegno:||Parigi|
|Titolo del libro:||European Neuropsychopharmacology|
|Appare nelle tipologie:||Relazione in Atti di Convegno|
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