Neuronal-derived exosomes can be utilized to show antidepressant response

As exosomes are a type of extracellular vesicle (EV) that carry molecular cargo, explained Dr Turecki, they can be isolated from the blood and both their contents and molecular signature of their originating cell can be analyzed.¹ EVs can cross the blood-brain barrier² and neural-derived small EVs (NDEVs) can be isolated in peripheral blood, providing a non-invasive look at the brain.³

Compared to brain-derived NDEVs from post-mortem tissue, plasma NDEVS have an almost 90% overlap in terms of their cargo, showing they are comparable. Genes found within NDEVS are mostly of neuronal and brain factors.³

Peripheral neural-derived extracellular vesicles might be used to investigate antidepressant response

In a study in Dr Turecki’s laboratory, while no difference was found in the total EV count between patients with depression and healthy controls, both total EVs and NDEVs were significantly smaller in the former. With antidepressant treatment, there was a significant increase in NDEV size in those that responded at 8 weeks, along with a significant increase in the number of EVs released.³

In the NDEV cargo, three of the significant micro RNAs (miRNA) were predictive of response to AD. These findings were replicated for two of the miRNAs in an independent antidepressant treated sample. These findings, explained Dr Turecki, point to promising miRNA targets to investigate in future studies.³

Regulation of mRNA translation involved in neuroinflammation has implications in depression

In people with major depressive disorder, there is evidence of an alteration in signaling pathways that control mRNA translation initiation, including decreased mammalian target of rapamycin (mTOR) in the prefrontal cortex (PFC) and decreased extracellular-signal-regulated kinase (ERK) in the hippocampus. In animal studies, these can be increased by antidepressants.⁴

Regulation of mRNA translation in neurons is important in synaptic plasticity and spine morphogenesis.⁵ In his talk, Dr Aguilar-Valles focused on the eukaryotic initiation factor 4F complex (eIF4F), which is regulated, in part, by mTORC1 at its binding protein.⁶ Using a mouse mutant for a single nucleotide in the 4E protein, Dr Aguilar-Valles and colleagues found this pathway was involved in activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and subsequent overexpression of brain located inflammatory mediations such as tumor necrosis factor-α (TNFα).⁷

Inflammation following aberrant mRNA translation initiation is associated with depressive symptoms

Decreased levels of the NF-kB inhibitor IkBα can lead to NF-kB overactivation, as identified in mice mutant for eIf4e phosphorylation.⁸ In work presented here, Dr Aguilar-Valles showed that brain expression of IkBα is controlled by the MAP kinase-interacting kinase 1 (MNK1)/2-eIF4E pathway. In the eIF4E knock-in mice, they found significant increases in TNFα along with microgliosis in the hippocampus and PFC, all indicative of inflammation. These mice also presented behavior indicative of depression, such as increased latency to feed in a novelty suppressed feeding condition and decreased exploration of the center of an open field.

This group also looked at neurotransmission in the PFC and found that serotonin response was severely blunted in the eIF4E knock-in mice. Using a dominant negative protein to block TNFα, such behavioral deficits were reversed, as was the induction of excitation in the PFC.

The endocannabinoid system in depression

Dr Comai posited that endocannabinoids are involved in symptoms of depression. The two main endocannabinoids, anandamide and 2-arachidonoylglycerol (2AG), are produced post-synaptically and then function pre-synaptically as ‘retrograde neuromodulators’.⁹

Here he presented work carried out in his laboratory that had the aim of investigating the potential relationship in people with depression between circulating endocannabinoid biomarkers and the tryptophan to 5-HT and kynurenine pathways.¹⁰ While 5-HT is not able to cross the blood brain barrier, peripheral tryptophan concentrations have been shown to accurately reflect 5-HT levels in the brain.¹¹

There is a potential role for endocannabinoids in the tryptophan degradation pathways

In Dr Comai’s study, higher degradation of circulating tryptophan to kyneurenine and higher levels of serum 2AG were found in patients with depression. Also found was a negative correlation between tryptophan and depression severity and a positive assocation between tryptophan degradation into kyneurenine and endocannabinoids. Additionally, good discrimination between the patient and controls group was found for biomarkers of degradation of tryptophan into kyneurenine. These data, Dr Comai concluded, “confirm the crosstalk between the endocannabinoid and 5-HT systems and their involvement in depression.”