Case 2 - cytokine x BDNF

Question 1

pro-inflammatory effects on BDNF levels

Answer 1

• Acute LPS treatment (induces inflammation) diminished the number of new neurons generated, impaired the proliferation of hippocampal precursor cells, and transiently reduced BDNF and NGF levels in the cortex and hippocampus.
• Circulating cytokines such as IL-1ß decrease adult hippocampal neurogenesis and produce depressive-like behaviors.
• People treated with IFN-α had lowered BDNF levels during treatment.

–> Inflammatory cytokines lead to reduced BDNF production and phosphorylation of TrkB, subsequently reducing ERK and PLCγ-1 signaling

Question 2

effects of low BDNF

Answer 2

increased neurodegenration
decreased neurogenesis
deceased neuronal surival
decreased neuronal plasticity

Question 3

purinic and other DAMP signalling

Answer 3

1. ATP/DAMPS/HSPs is released in response to psychological stress, due to increased glutamate
2. binds to the P2X7 receptor (P2X7R) on microglia.
3. The efflux of K+ caused by ATP induces NLRP3 activation
4. IL1b release
5. TNFa release
6. NFkB activation in NPS –> reduced neurogenesis and plasticity
7. behavioural deficits

Question 4

IDO pathway and stress

Answer 4

Pro-inflammatory cytokines that are increased in chronic stress, stimulate the kynurenine pathway.
- Neurotoxic quinolinic acid (QA) is one of the metabolites of this pathway. It acts as a NMDA receptor agonist.
- NMDA receptor activates its downstream target, being JN kinase.
- Activation of this kinase was found to be associated with reduced TrkB/BDNF levels. –> proBDNF-p75 receptor signaling pathway. Downstream effects of this pathway are apoptosis and reduced neurogenesis and NFkB activation and cytokine production

Question 5

peripheral immune stimulation and BDNF

Answer 5

cytokines reach the brain in 4 ways leading to reduced BDNF production

Question 6

pro-inflammatory SERT-dependent BDNF modulation

Answer 6

• Pro-inflammatory cytokines enhance SERT activity → increased re-uptake of serotonin → reduced extracellular serotonin levels → reduced serotonin signaling → reduced CREB-dependent BDNF expression → decreased BDNF levels
• SSRI (antidepressants) block SERT and increase extracellular serotonin levels → enhanced CREB dependent BDNF gene expression