Neuronal plasticity and neurotrophic factors in drug responses

Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and other members of the neurotrophin family, are central mediators of the activity-dependent plasticity through which environmental experiences, such as sensory information are translated into the structure and function of neuronal networks. Synthesis, release and action of BDNF is regulated by neuronal activity and BDNF in turn leads to trophic effects such as formation, stabilization and potentiation of synapses through its high-affinity TrkB receptors. Several clinically available drugs directly activate neurotrophins and neuronal plasticity. In particular, antidepressant drugs rapidly activate TrkB signaling and gradually increase BDNF expression, and the behavioral effects of antidepressants are mediated by and dependent on BDNF signaling through TrkB at least in rodents. These findings indicate that antidepressants, widely used drugs, effectively act as TrkB activators. They further imply that neuronal plasticity is a central mechanism in the action of antidepressant drugs. Indeed, it was recently discovered that antidepressants reactivate a state of plasticity in the adult cerebral cortex that closely resembles the enhanced plasticity normally observed during postnatal critical periods. This state of induced plasticity, known as iPlasticity, allows environmental stimuli to beneficially reorganize networks abnormally wired during early life. iPlasticity has been observed in cortical as well as subcortical networks and is induced by several pharmacological and non-pharmacological treatments. iPlasticity is a new pharmacological principle where drug treatment and rehabilitation cooperate: the drug acts permissively to enhance plasticity and rehabilitation provides activity to guide the appropriate wiring of the plastic network. Optimization of iPlastic drug treatment with novel means of rehabilitation may help improve the efficacy of available drug treatments and expand the use of currently existing drugs into new indications.