University of Helsinki, Helsinki 2006
Brain TrkB neurotrophin receptor as a target for antidepressant treatments
Doctoral dissertation, October 2006.
Reduced actions of brain-derived neurotrophic factor (BDNF) are linked to the pathophysiology of depression whereas antidepressants induce BDNF synthesis together with neuroplastic alterations in the brain. Still the molecular mechanisms regulating the effects of antidepressants on BDNF synthesis are largely obscure and it is not well known whether this BDNF induction leads to the signaling of BDNF receptor TrkB in vivo. By using an antibody against autophosphorylated TrkB, we show that pharmacologically diverse antidepressants induce TrkB activity in the rodent anterior cingulate cortex (ACC) and hippocampus (HC). Lithium (Li+), an antimanic and antidepressant-augmenting agent, produces similar changes in TrkB activity in the ACC. ACC and HC are two key brain areas implicated in depression and antidepressant action. Given that clinically used antidepressants and Li+ act in a lag-time manner, it is interesting that the effects of these agents on brain TrkB signaling are observed rapidly after a single drug administration. Antidepressant-regulated TrkB-induction specifically leads to the activation of phospholipase-Cγ1 (PLCγ1) which in turn, and likely in concert with monoaminergic signaling events, induces the phosphorylation of CREB (cAMP related element binding protein). Through the activation of PLCγ1-CREB cascade, antidepressants may regulate synaptic plasticity and the release and synthesis of BDNF itself. Interestingly however, electroconvulsive shock (ECS), among the most potent antidepressant therapy, rapidly reduces TrkB signalling in the rodent prefrontal cortex (PFC) even in situations were endogenous BDNF levels are high. In contrast, ECS induces the ERK (extracellular signal-regulated kinase) neurotrophic pathway in the rodent PFC. The behavioural studies revealed that sustained increase in TrkB signalling is characterized with antidepressant-like behaviour in a rodent model of behavioural despair, the forced swim test (FST). In contrast, basal behaviour of TrkB deficient mice is normal but these mice do not respond to serotonergic antidepressant in the FST. Altogether, the present results provide compelling evidence that chemical antidepressants produce rapid neurotrophic actions through the TrkB-PLCγ1-CREB signaling in the rodent brain and suggest that these changes initiate plastic responses in the neuronal networks implicated in depression.
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© University of Helsinki 2006
Last updated 28.09.2006