BDNF signaling in context: From synaptic regulation to psychiatric disorders

Abstract

Brain-derived neurotrophic factor (BDNF) is a neuropeptide that plays numerous important roles in synaptic development and plasticity. While its importance in fundamental physiology is well established, studies of BDNF often produce conflicting and unclear results, and the scope of existing research makes the prospect of setting future directions daunting. In this review, we examine the importance of spatial and temporal factors on BDNF activity, particularly in processes such as synaptogenesis, Hebbian plasticity, homeostatic plasticity, and the treatment of psychiatric disorders. Understanding the fundamental physiology of when, where, and how BDNF acts and new approaches to control BDNF signaling in time and space can contribute to improved therapeutics and patient outcomes.

Figure 1:. BDNF-TrkB receptor binding leads to activation of distinct downstream signaling pathways

The binding of BDNF to its high affinity TrkB receptor induces the activation of distinct signaling pathways. The TrkB receptor has several phosphorylation sites, which can activate several unique pathways at both the pre- and post-synaptic specializations. The PI3K/mTOR and MAPK pathways can activate protein translation (including BDNF, CAMKII, and Arc) at dendritic boutons. The PLC-gamma and MAPK pathways can impact calcium influx, which in turn lead to activation of CAMKII and trigger and subsequent synaptic plasticity (i.e. synaptic strengthening via increased AMPAR trafficking). At presynaptic terminals, activation of TrkB leads to changes in neurotransmitter release (i.e. increased release at hippocampal neurons). All three downstream pathways have been implicated in this effect. The action of BDNF at synapses is specific to its binding of TrkB receptors, though the location at and circumstances under which this binding occurs can lead to widely different effects on synaptic activity.

Figure 2:. Schematic demonstrating the pre- and postsynaptic actions of BDNF-TrkB activity

The release and action of BDNF is precisely regulated and has specific effects depending on the location of its binding to TrkB receptors. After BDNF is cleaved into its mature form, it can be trafficked to both presynaptic boutons and postsynaptic dendritic sites, where it is stored in dense core vesicles. Upon arrival to the synapse, BDNF is released with the help with SNARE proteins such as SNAP25, SNAP47, and synaptobrevin-2 (Syb2). Upon release into the extracellular space, BDNF then acts locally on cis- and trans-synaptic TrkB receptors. Activation of receptors at different locations differentially affects processes such as synaptogenesis to synaptic plasticity. Once BDNF binds to its high affinity TrkB receptor, it can activate downstream TrkB signaling pathways, as well as be endocytosed into an BDNF-TrkB containing endosome to be trafficked for further intracellular signaling or recycling of receptors.

Figure 3:. Principles of Hebbian vs Homeostatic Forms of Plasticity

Hebbian plasticity, including LTP, is the most classically studied form of plasticity (A). It occurs in a positive feedback loop, whereby an axon repeatedly and persistently fires to induce an increase in the baseline efficiency of neurotransmission. It is input specific, associative and occurs on a rapid timescale of seconds to minutes. Homeostatic plasticity, on the other hand, counters the direction of stimuli over the course of hours to days to return a neuron to its homeostatic set point (B). This change is global and multiplicative, such that synapses that have a higher efficacy of transmission at baseline will experience a greater change in homeostatic plasticity. This is represented in the figure by synapses with a larger number of receptors having a higher baseline level of transmission. These more efficacious synapses experience a larger change in synaptic scaling upon chronic increases or decreases in activity, as shown by a darker shade of color (red for downscaling, yellow for upscaling) at the synapse.

Figure 4:. Importance of the acute versus chronic nature of BDNF activity on plasticity

BDNF plays an important role in synaptic scaling, which involves the modulation of synaptic strength to counter chronic changes in activity, as a mechanism to maintain the relative strength of synaptic connections. Ketamine, a rapid antidepressant that inhibits NMDA receptors, induces a rapid increase in BDNF that leads to synaptic upscaling. On the other hand, lithium is a mood stabilizer that is an effective treatment for bipolar disorder. Lithium has been found to induce chronic, lasting increases in BDNF, and furthermore, has been shown to induce synaptic downscaling. Though both drugs increase BDNF levels, differences in the time course of this increase can elicit directly opposing effects. Furthermore, different types of synapses respond differentially to BDNF (i.e. inhibitory versus excitatory synapses). Taking into account the direction of change, the timescale, and the type of synaptic formations can hugely impact the effect of BDNF at synapses and ultimately behavior.

Figure 5:. Effects of psychiatric drugs on BDNF activity in different brain regions

BDNF plays a critical role in the mechanism underlying psychiatric treatment, notably with antidepressants and mood stabilizers. Antidepressants, including SSRIs and ketamine, have been found to increase BDNF in the cortex and hippocampus, while decreasing protein levels in the nucleus accumbens and ventral tegmental area. Mood stabilizers, including lithium, have been found to increase BDNF levels in many brain regions including the cortex, hippocampus, ventral tegmental area, amygdala, and nucleus accumbens. The effect of psychiatric drugs on BDNF levels depends on the brain region studied, demonstrating a circuit level involvement of BDNF and psychiatric treatments.