Role of BDNF in the pathophysiology and treatment of depression: Activity-dependent effects distinguish rapid-acting antidepressants

Abstract

The pathophysiology and treatment of depression have been the focus of intense research and while there is much that remains unknown, modern neurobiological approaches are making progress. This work demonstrates that stress and depression are associated with atrophy of neurons and reduced synaptic connectivity in brain regions such as the hippocampus and prefrontal cortex that contribute to depressive behaviors, and conversely that antidepressant treatment can reverse these deficits. The role of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), has been of particular interest as these factors play a key role in activity-dependent regulation of synaptic plasticity. Here, we review the literature demonstrating that exposure to stress and depression decreases BDNF expression in the hippocampus and PFC and conversely that antidepressant treatment can up-regulate BDNF in the adult brain and reverse the effects of stress. We then focus on rapid-acting antidepressants, particularly the NMDA receptor antagonist ketamine, which produces rapid synaptic and antidepressant behavioral actions that are dependent on activity-dependent release of BDNF. This rapid release of BDNF differs from typical monoaminergic agents that require chronic administration to produce a slow induction of BDNF expression, consistent with the time lag for the therapeutic action of these agents. We review evidence that other classes of rapid-acting agents also require BDNF release, demonstrating that this is a common, convergent downstream mechanism. Finally, we discuss evidence that the actions of ketamine are also dependent on another growth factor, vascular endothelial growth factor (VEGF) and its complex interplay with BDNF.

Keywords: ketamine; neurotrophic factor; stress; synaptic plasticity.

Figure 1.. Processing of BDNF and receptor coupled signaling pathways.

BDNF gene expression is controlled by multiple signaling pathways included neuronal activity. BDNF transcripts can be translated in the soma or transported to other cellular compartments, notably dendrite as well as axon terminals. The transcripts are translated to pre-proBDNF which undergoes processing and cleavage to proBDNF, which is further processed by to mature BDNF. Mature BDNF is associated with synaptic plasticity and undergoes activity dependent release, while proBDNF undergoes low levels of constitutive released. The BDNF prodomain contains a common single nucleotide polymorphism, BDNF Val66Met. The Met allele impairs the trafficking and processing of proBDNF and therefore reduces activity dependent release of mature BDNF. Mature BDNF binds to the TrkB and activates downstream signaling pathways associated with synaptic plasticity, synapse formation, neuronal differentiation and survival. The proBDNF isoform binds to the p75 neurotrophin receptor (p75NTR) and activates a different set of downstream signaling pathways that are linked with disruption of synaptic plasticity, long-term depression, synaptic pruning, decreased growth and apoptosis.

Figure 2.. Model for the loss of spine synapses in stress and depression: rapid reversal by ketamine and comparison with typical monoamine reuptake inhibitor antidepressants.

Synaptic number and function in the PFC and hippocampus are maintained by homeostatic mechanisms, and proper control of synaptic connectivity in these regions is required for control of mood as well as other cortical functions. This includes activity dependent regulation of synaptic proteins, such as GluA1, PSD95, and synapsin 1. Chronic stress exposure (left) decreases the number and function of spine synapses in the PFC and hippocampus, in part via decreased BDNF expression, and decreased TrkB-mTORC1 signaling. Increased expression of a negative regulator of mTORC1 signaling, regulated in DNA damage and repair (REDD1) contributes to this effect. Antidepressant treatment (right) increases BDNF and reverses the effects of stress and depression. The NMDA receptor antagonist ketamine causes a rapid burst of glutamate that causes activity dependent release of BDNF resulting in rapid induction of synapse number and function via stimulation of TrkB-mTORC1 signaling and increased translation of synaptic proteins including GluA1. In contrast, typical antidepressants including the monoamine reuptake inhibitors (e.g., SSRI, SNRI) produce a slow induction of BDNF expression and constitutive release over several weeks of treatment, which contributes to slow adaptive changes that reverse the effects of stress and produce antidepressant responses. There is no evidence that typical antidepressants cause activity dependent release of BDNF, which is necessary for the rapid antidepressant actions of ketamine. Depression as well as relapse that occurs after 7 to 10 days in patients treated with ketamine could result from environmental factors such as sustained or uncontrollable stress or other susceptibility factors that decrease the stability of new synaptic connections.