Brain-derived neurotrophic factor (BDNF) is a key protein whose expression is thought to be regulated by chronic antidepressant administration during the treatment of mood and anxiety disorders. Antidepressants, including serotonin-selective reuptake inhibitors (SRIs) have been postulated to reverse hippocampal neuronal atrophy and increase neurogenesis via BDNF-dependent mechanisms. Serotonin reuptake is also under genetic control. In humans, serotonin transporter (SERT) gene expression is variable due to a common promoter polymorphism such that serotonin reuptake is decreased by 40% in ~70% of the normal human population. This reduction is correlated with increases in anxiety-related personality traits and susceptibility to stress-associated depression. In addition to its purported role in the mechanism of action of antidepressants, regulation of BDNF is important in cellular learning and memory, seizure, schizophrenia, drug abuse and Alzheimer's disease. The role of BDNF in these, as well as other important brain functions, in combination with the complexity of the upstream elements in the BDNF gene leads us to theorize that expression of alternate BDNF transcripts is highly regulated in brain regional and cell signaling dependant ways. We specifically hypothesize that serotonin exerts control over the expression of individual BDNF transcripts and that this occurs differently in response to SRI-mediated versus constitutive reductions in serotonin reuptake. Here, we aim to (1) map the expression patterns of the nine putative mouse BDNF splice variants in the brain by RT-qPCR and in situ hybridization and (2) investigate regiospecific regulation of individual BDNF mRNA variants by pharmacologic (SRI) versus genetic (SERT knockout mice) alterations in serotonin reuptake. Mapping the regional expression patterns of alternate BDNF transcripts in the mouse brain is critical for future studies aimed at leveraging the many genetically engineered mouse models available for investigating the molecular aspects of psychiatric and degenerative disorders in which BDNF is theorized to play a key role. Moreover, understanding the control of individual BDNF splice variants by two clinically relevant forms of reduced serotonin reuptake will facilitate the design of new treatments for depression and anxiety disorders targeted at regulating BDNF expression via specific serotonin receptor subtypes, intracellular signaling pathways and transcription factors. ? ? ?
| Bressler, Amanda; Blizard, David; Andrews, Anne (2010) Low-stress route learning using the Lashley III maze in mice. J Vis Exp : |
