Final Report Summary - IPLASTICITY (Induction of juvenile-like plasticity in the adult brain) Neuronal networks are tuned to optimally represent external and internal milieu through neuronal plasticity during critical periods of juvenile life. After the closure of the critical periods, plasticity is considered to be much more limited. My research group has shown that critical period-like plasticity can be reactivated in the adult mammalian brain by pharmacological treatment with the antidepressant fluoxetine. This project investigated the neurobiological mechanisms underlying this drug-induced juvenile-like plasticity, or iPlasticity.We have previously shown that antidepressant drugs activate the signalling of Brain-derived neurotrophic factor (BDNF) through its receptor TrkB and that BDNF signalling is necessary for iPlasticity. In this project we have investigated how antidepressants activate TrkB receptors and in which neurons the TrkB receptors that are critical for iPlasticity reside. We have found that antidepressants disrupt an interaction between TrkB receptor and a protein phosphatase that normally suppresses TrkB activity, thereby inducing BDNF signalling. We have further shown that TrkB receptors on parvalbumin-containing interneurons are critical for iPlasticity and revealed the molecular and cellular mechanisms that TrkB receptors activate in these cells. We have systematically utilized and expanded our resources as a leading lab in BDNF effects in adult brain and created novel controlled transgenic models, genomics and proteomics, we have revealed the role of BDNF signalling through TrkB in iPlasticity. The other BDNF receptor, p75, acts as a functional antagonist of TrkB signalling, promoting cell death and synapse loss, and previous findings suggest that p75 levels are increased after brain insults. In this project, we have created the first mouse model that enables the monitoring of p75 receptor signalling in vivo and we have shown that p75 signalling is indeed enhanced in brain ischemia. Understanding the neurobiological background of iPlasticity is critical for the development of therapies that take advantage of increased BDNF signalling and promoted plasticity. In particular, iPlasticity has potential to transform the treatment of mood disorders. Future treatment of depression will likely involve a combination of antidepressant treatment and optimized rehabilitation strategies to take full advantage of iPlasticity.
