Cyclic AMP response element binding protein and brain-derived neurotrophic factor: molecules that modulate our mood?

Abstract

Depression is the major psychiatric ailment of our times, afflicting approximately 20% of the population. Despite its prevalence, the pathophysiology of this complex disorder is not well understood. In addition, although antidepressants have been in existence for the past several decades, the mechanisms that underlie their therapeutic effects remain elusive. Building evidence implicates a role for the plasticity of specific neuro-circuitry in both the pathophysiology and treatment of depression. Damage to limbic regions is thought to contribute to the etiology of depression and antidepressants have been reported to reverse such damage and promote adaptive plasticity. The molecular pathways that contribute to the damage associated with depression and antidepressant-mediated plasticity are a major focus of scientific enquiry. The transcription factor cyclic AMP response element binding protein (CREB) and the neurotrophin brain-derived neurotrophic factor (BDNF) are targets of diverse classes of antidepressants and are known to be regulated in animal models and in patients suffering from depression. Given their role in neuronal plasticity, CREB and BDNF have emerged as molecules that may play an important role in modulating mood. The purpose of this review is to discuss the role of CREB and BDNF in depression and as targets/mediators of antidepressant action.

Figure 1

The CREB cascade. CREB is regulated by diverse signalling pathways, and can thus serve as a central integrator for the actions of numerous external stimuli, including antidepressants (ADT). Antidepressants which have distinct acute targets are known to recruit several signal transduction pathways, including cyclic AMP – protein kinase A (cAMP-PKA) cascade, the MAP kinase signalling pathway (MEK/ERK) as well as calcium and phospholipase C (PLC) signalling. A downstream consequence of enhanced CREB function is thought to be the increased expression of target genes like the neurotrophin, brain-derived neurotrophic factor (BDNF), and neuropeptide Y (NPY), which may contribute to the ADT-mediated changes in structural plasticity and behaviour.

Figure 2

Sagittal schematic of the adult rat brain. Shown are the two major circuits, regulated by the CREB-BDNF cascade that, have a relevance to depression. The hippocampus (Hip) projects to the hypothalamus (Hypo) via a multi-synaptic pathway. This circuit is thought have a critical inhibitory control over the hypothalamo-pituitary-adrenocortical stress response pathway. The other circuit where CREB and BDNF have been shown to perturb depression-related behaviours is the meso-limbic dopaminergic pathway. This pathway consists of dopaminergic neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens (NAc) and modulate reward perception.

Figure 3

Role of CREB and BDNF in hippocampal structural plasticity in response to antidepressants and in animal models of depression. Shown are the hippocampal subfields, where dentate gyrus (DG) neurogenesis and CA subfield dendritic branching is regulated by both antidepressants and in depression models. While antidepressants enhance CREB-BDNF and promote neurogenesis and dendritic sprouting, animal models of depression are associated with a decline in CREB-BDNF, dendritic atrophy and decreased neurogenesis.

Figure 4

The role of the BDNF-CREB cascade in the ventral tegmental area (VTA) – nucleus accumbens (NAc) pathway. Enhanced BDNF-CREB signalling in the NAc in animal models of stress and depression is associated with increased dynorphin expression. Dynorphin, through a feedback inhibitory loop, activates κ opioid receptors on VTA neurons and results in an inhibitory effect on the dopaminergic neurons projecting from the VTA to the NAc. Decreased activation of the VTA-NAc pathway is associated with the pro-depressive effects induced by overexpression of CREB-BDNF in this circuit.