Case 2 - HPA x BDNF

Question 1

GR TrkB transactivation

Answer 1

After GC has entered the cell and is bound to GR to create the GC-GR complex, GC-GR will interact with TrkB either through direct intracellular binding, causing TrkB autophosphorylation (& subsequent downstream cascades), or through interaction with downstream pathways of TrkB (PI3K/Akt, MAPK, PLCγ). This process is referred as GR-TrkB transactivation and has been proposed to be similar to transactivation of Trk by G-protein-coupled receptors.
In transient increase of GCs (especially if dosage is low) TrkB transactivation can lead to results similar to BDNF-TrkB activation (neuroprotective). At high doses and for prolonged time, GCs become neurotoxic, leading to glutamatergic excitotoxicity & apoptosis, or often, they inhibit the downstream pathways that work in neuronal survival

Question 2

brain region specific effects of BDNF&stress

Answer 2

Hippocampus
In the hippocampus chronic and acute stress lead to down regulation of BDNF and a reduction of overall neuroplasticity, depending on the duration of stress also neuronal death and shrinkage of hippocampal volume.

Prefrontal Cortex
Chronic stress causes medial PFC neurons to show debranching and shrinkage of dendrites associated with cognitive rigidity and lower BDNF levels while orbitofrontal neurons expand dendrites and may be related to increased vigilance

The medial amygdala under chronic stress shows loss of spines which has been associated with lower BDNF levels and increased anxiety and PTSD-like behaviors

Question 3

GC regulation of BDNF expression

Answer 3

• BDNF transcription can be modulated by GCs either by direct binding to putative glucocorticoid response elements (GREs) present on the promoter region of the BDNF gene (needs replication to be validated) OR by interfering with the activity of other transcription factors reported to contribute to BDNF transcription, such as the activator protein-1 (AP-1) complex and CREB.
• In addition to the transcriptional regulation of BDNF, GCs can also potentially alter the translation of the BDNF gene by modulating the activity of the translational machinery

GCs can modulate the levels or the activity of the intracellular and extracellular proteases and thus regulate the levels of available mature BDNF.
* GCs may regulate BDNF by influencing its secretion

Question 4

ADs and HPA negative feedback

Answer 4

Antidepressants (ADs) targeting the normalizing of negative feedback
Clinical studies show that successful antidepressant treatment is associated with the resolution of the impairment in the HPA axis negative feedback by GCs.
* Long-term AD treatment upregulated GR and MR in the brain – including the hippocampus and the hypothalamus, and decreased basal and stress-induced glucocorticoid secretion.
* Most studies used TCAs
* Studies investigating the effect of SSRIs like fluoxetine have found that chronic treatment with these ADs upregulates MR expression but does not change GR expression.

Question 5

BDNF and ADs’ effects

Answer 5

Administration of antidepressant drugs increases the expression of BDNF in the hippocampus and the PFC

• Moreover, infusion into the DG or CA3 in the hippocampus but not CA1 resulted in antidepressant-like effects, suggesting that these regions may be key for antidepressant effects acting via BDNF

In patients with MDD, the BDNF SNP (val66met) and other SNPs were linked to a reduced response to antidepressant treatment.