Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder

Thomas Larrieu, Charline Carron, Fabio Grieco, Crystal Weber, Kyllian Ginggen, Aurélie Delacrétaz, Hector Gallart-Ayala, Mumeko Tsuda, Heather A. Cameron, Chin B. Eap, Julijana Ivanisevic, Pierre Magistretti, Ludovic Telley, Alexandre Dayer, Camille Piguet, Nicolas Toni

Posted on: 4 December 2024

Preprint posted on 19 August 2024

New research reveals how blood platelets can prevent neurogenesis in stressed adults 🩸🧠

Selected by Harvey Roweth

Categories: animal behavior and cognition, cell biology, molecular biology, neuroscience

Background

Our brains are continuously generating new neurons, which allows us to adapt to and recover from stressful events. Environmental triggers such as inflammation and chronic stress can impair neurogenesis in the hippocampus of adult brains, reducing both neural plasticity and our tolerance of stress. Anxious people often react stronger to environmental stressors, leaving them particularly vulnerable to reduced neurogenesis and associated mood disorders like depression. Therefore, preserving or even promoting adult neurogenesis may limit the effects of mental illnesses including anxiety disorders and other psychiatric conditions.

Unlike embryonic development, neurogenesis is restricted to either the subventricular zone of the lateral ventricle, or the dentate gyrus of the hippocampus in adult mammals. Here, neural progenitor cells (NPCs) proliferate within a “neurogenic niche”, a complex microenvironment locally controlled by neurons, microglia, astrocytes, oligodendrocytes, pericytes and blood vessels.¹ In this preprint, Larrieu and colleagues combine a novel in vitro assay with pre-clinical and patient serum samples to explore how circulating blood factors affect adult neurogenesis in the context of stress and anxiety.

Key findings

By treating NPCs with serum from both highly anxious mice and young adults with anxiety, the authors show that serum from anxious individuals can reduce neurogenesis in vitro.
Metabolomic analysis revealed increased serum levels of the signalling lipid lysophosphatidic acid 16:10 (LPA16:0) in anxious mice and humans, which reduces adult NPC proliferation via the LPA receptor, LPA₁.
Platelet depletion reduced circulating LPA16:10 in mice and increased both stress resilience and adult neurogenesis.

Why I found this preprint interesting

During my PhD, I studied neurotransmitters in platelets and was surprised at how these circulating blood cell fragments can mimic the aspects of neurobiology. More recently, focus has moved onto how platelets regulate the central nervous system, particularly the reversal cognitive decline in aged mice by increasing hippocampal neurogenesis.^{2, 3} Interestingly, this pre-print suggests that the platelets instead impair neurogenesis in younger adults experiencing stress, highlighting their multifaceted and complicated contributions to neurobiology.
The authors develop an in vitro blood-brain axis (BBA) assay, allowing them to bypass expensive and technical animal procedures such as blood transfusion and parabiosis. While this assay lacks the complexity of the neurogenic microenvironment, it appears to offer a complimentary tool for screening biomarkers of anxiety.

Figure 1: The author’s proposed mechanism of how platelet-derived lysophosphatidic acid 16:10 (LPA16:0) limits the proliferation of adult neural progenitor cells (NPCs) through binding to the LPA₁ receptor.

References

Bjornsson CS, Apostolopoulou M, Tian Y, Temple S. It takes a village: Constructing the neurogenic niche. Dev Cell. 2015;32:435-446
Schroer AB, Ventura PB, Sucharov J, Misra R, Chui MKK, Bieri G, et al. Platelet factors attenuate inflammation and rescue cognition in ageing. Nature. 2023;620:1071-1079
Leiter O, Brici D, Fletcher SJ, Yong XLH, Widagdo J, Matigian N, et al. Platelet-derived exerkine cxcl4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice. Nat Commun. 2023;14:4375

Tags: anxiety, neurogenesis, platelet, stress

doi: https://doi.org/10.1242/prelights.39073

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Author's response

Nicolas Toni shared

My discussion with the authors

While an excellent proof-of-principal, platelets are required for haemostasis and their depletion in humans is not a clinically viable option. Do you hypothesise that antiplatelet agents that prevent LPA16:0 release or drugs that partially reduce platelet counts could be considered as long-term treatment options in the future?

“The normal platelet count in adults ranges from 150,000 to 450,000 platelets per microliter of blood. Although platelets are primarily recognized for their role in the clotting process, where they are critical for hemostasis, it is estimated that less than one-tenth of the circulating platelet population is actually required to ensure proper clot formation and maintain hemostasis (PMID 35609283). Thus, the therapeutic window for reducing platelet-mediated LPA16:0 release without reaching a level that would impair blood clotting is high. Therefore, a controlled reduction in platelet activity could indeed allow for the modulation of LPA16:0 levels while preserving essential hemostatic function, offering a promising avenue for therapeutic intervention aimed at increasing adult neurogenesis and stress resilience.”

Platelets are also major serum sources of factors associated with promoting adult hippocampal neurogenesis (e.g., serotonin, platelet factor 4). Do you believe that platelet LPA16:0 outcompetes these effects in cases of stress?

“The increased stress resilience that we observed after platelets depletion suggests that indeed, in our experimental conditions, the effect LPA16:0 may be greater than the effect of other platelet-derived proneurogenic molecules such as serotonin or platelet factor 4. One has to consider however that the release of specific factors may depend on the environmental context. For instance, physical activity stimulates PF4 release, enhancing neurogenesis (PMID 30905740), while conditions that increase anxiety may trigger higher LPA16:0 levels (PMID 16625099), shifting the balance toward neurogenesis inhibition. Thus, the net effect of platelet depletion on adult neurogenesis may depend on the conditions that activated platelets in the first place. It is unclear at this stage how these different signaling mechanisms may interact with each other to regulate adult neurogenesis and further, carefully designed experiments are required to disentangle them.”

You show that LPA16:10 has a dose-dependent effect on adult NPCs, where only low (30 nM) concentrations reduce proliferation. How do these concentrations relate to those in circulation, and more importantly the hippocampus?

“Concentrations in vitro are difficult to compare to concentrations in vivo, due to numerous factors that interfere with drug exposure, such as clearance, pharmacokinetics and in the brain, blood-brain barrier permeability. Adult neural stem cells are preferentially exposed to blood-circulating molecules (PMID 27091993) and therefore, molecules that do not necessarily cross the BBB still interact with hippocampal stem cells (PMID 32496193). In our in vitro experiment, we used a non-hydrolysable form of LPA16:0 (cLPA16:0) with a longer half-life than endogenous LPA16:0, which is of a few minutes. It means that a lower dose is likely sufficient to have an effect on stem cell proliferation. When we administered cLPA16:0 chronically to reduce adult neurogenesis, we measured a serum concentration in the range of 10-20nM, which is comparable to the concentrations we used in vitro. Thus, with cLPA16:0, the in vivo effect is observed at a dose that is also active in vitro.”

Given that activated platelets from both non-stressed and stressed individuals will release LPA16:10 when creating serum, do you hypothesize that LPA16:10 levels are higher in the platelets of stressed individuals?

“We indeed postulate that individuals suffering from anxiety might exhibit elevated levels of LPA16:0 in their platelets. To tackle this question, it would be interesting to collect blood samples from patients diagnosed with anxiety disorders, isolate their platelets, and then precisely measure LPA16:0 levels. This analysis could be conducted under two conditions: first in a baseline state, and then following platelet activation. This study would allow us to compare LPA16:0 levels between these two states and potentially establish a link between platelet LPA16:0 production and anxiety.”

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