Fisiologia e fisiopatologia di BDNF: verso lo sviluppo di nuove strategie terapeutiche per alcune delle principali malattie neuro-psichiatriche

Neuropsychiatric disorders represent major causes of disability worldwide, with treatments often unsatisfactory, and still obscure biological underpinnings. Pathophysiology is envisaged as due to the interaction of genetic vulnerability with environmental events. Animal models are particularly useful as they may provide a defined transgenic background replicating human mutations and are amenable to test the role of specific environmental manipulations in gene-environment (GxE) models.



Brain Derived Neurotrophic Factor (BDNF), a key factor in neuroplasticity, gene expression, synaptic function and cognition, has been implicated in the pathophysiology of various neuropsychiatric and neurodegenerative disorders. The BDNF Val66Met transgenic mouse (obtained through a collaboration with F.S. Lee; Cornell Univ., NY) is the only existing animal model that recapitulates the phenotypic hallmarks of the BDNF Val66Met human polymorphism. Both human and mice BDNF^Met allele carriers show reduced hippocampal volume, cognitive deficits, and increased anxiety-related behaviour. This Unit and UO1 have recently traced down differential epigenetic changes in BDNF^Met/Met mice to functional changes in BDNF-6 dendritic translocation and secretion, a deficit that may be linked to pathophysiological features in mice and men (Mallei et al., submitted).



Main goal of this Unit will be to perform a genome-wide epigenetic analysis of an innovative GxE animal model of neuropsychiatric vulnerability (BDNF^Met/Met + CSC chronic stress). We will subject BDNF^Met/Met and BDNF^Val/Val mice to a validated protocol of chronic psycho-social stress (CSC, Slattery et al., 2011), to reproduce the GxE interaction that is thought to be crucial for pathogenesis. By performing a complete epigenetic screen using genome-wide ChIP-Seq analysis, we will identify: (1) genes activated/repressed by the presence of the human BDNF polymorphism; (2) genes activated/repressed by CSC in the context of genetic vulnerability of BDNF^Met/Met mice; (3) morphological and functional consequences of epigenetic changes, allowing to identify possible biomarkers of human pathology and putative drug targets.



It is expected that the proposed genome-wide analysis of this GxE model will disclose epigenetically regulated changes in the expression and function of key genes involved in BDNF-related pathology and, possibly, a number of putative drug targets for further investigation.