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 activitydependent 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.

Cortical and raphe GABAA, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine

“…An increase in GABA-release as found here in the mPFC, appears to contradict this main hypothesis. It is proposed that the resulting burst of glutamate may lead to BDNF release and the sustained release of both glutamate and GABA (Duman et al, 2019). Such an upregulated GABA synaptic function, as presented here in mice, is in line with deficits of GABA measured in depressed patients (Sanacora et al,…”

“…Ketamine selectively antagonizes these GABAergic interneurons to excitatory synapses leading to the loss of the tonic inhibition, thus increasing the burst of pyramidal glutamatergic neurons, leading to the release of mature Brain-Derived Neurotrophic Factor, which is required for the antidepressant-like activity of ketamine (Liu et al, 2012). However, this glutamate burst induces synaptic remodeling and resetting of glutamate and GABA systems (Duman et al, 2019). An increase in GABA-release as found here in the mPFC, appears to contradict this main hypothesis.…”

“…Artigas's group demonstrated that 5-HT release in the mPFCx depends on the excitatory glutamatergic transmission (Lopez-Gil et al, 2012). Ketamine triggers a cascade of neuronal adaptation involving the mammalian target of rapamycin (mTOR) pathway in the mPFC and activates synaptogenesis in an α-amino-3-hyroxy-5-methyl-4-isoxazolepropionic-acid-receptor-(AMPA-R)-dependent manner (Li et al, 2010;Duman et al, 2016Duman et al, , 2019. Upregulation of AMPA-R synaptic expression has been described in rodents within 24 hours after ketamine treatment (Zanos et al, 2016).…”

The physiology of regulated BDNF release

“…Ketamine-induced BDNF release was blocked in the presence of AMPA receptor inhibitors but also in the presence of L-type VGCC inhibitors (Lepack et al 2014). In this study, increased glutamatergic transmission induced by ketamine application was discussed as a reason for induction of BDNF release (Duman et al 2019;Lepack et al 2014). However, the molecular mechanisms underlying action of ketamine are not well understood (Lester et al 2012;Wei et al 2020).…”

Blues in the Brain and Beyond: Molecular Bases of Major Depressive Disorder and Relative Pharmacological and Non-Pharmacological Treatments

“…Among the many, a key role has been attributed to BDNF, which expression levels are increased by all the ADs, both in crucial CNS areas, such as the prefrontal cortex and the hippocampus, and in peripheral tissues such as plasma and serum. BDNF has been shown to be required for antidepressant response, and an increase in its expression levels has been observed after prolonged, but not acute, AD administration, consistent with the time course required for the onset of therapeutic effects [29,110,119,120]. After chronic SSRI treatment, an increase in the expression of other neurotrophic factors, such as the vascular endothelial growth factor (VEGF) and the fibroblast growth factor 2 (FGF2), were reported [29,110,121].…”