Trans-neuronal spreading of growth and survival via neuron-derived extracellular vesicles

Anna Antoniou1, Julia Lindlar1, Lalit Kaurani2, Kristin Oberländer3, Andre Fischer2, Anja Schneider4

2 DZNE Göttingen
3 DZNE Bonn
4 DZNE Bonn and UKB

Extracellular vesicles (EVs) are secretory vesicles containing non-coding RNAs, proteins and lipids. Recent work has demonstrated the functional transfer of EVs between cells in several biological contexts, thereby placing EVs as novel mediators of cell communication. In the brain, EVs were shown to mediate communication between neurons and non-neuronal cells and the spreading of toxic proteins in models of neurodegenerative diseases. Whether and how EVs contribute to inter-neuronal communication under physiological conditions remains unclear. We isolated small EVs from primary neurons and examined their composition and function during brain-derived neurotrophic factor (BDNF)-dependent development. BDNF shifted the composition of small EVs towards growth-promoting and neuroprotective proteins and microRNAs; non-coding RNAs that block the translation of target mRNAs thereby regulating compartmentalized gene expression. In agreement with this data, treatment of naïve developing hippocampal neurons with BDNF-stimulated EVs led to an increase in neuronal dendrite complexity and blocked glutamate-induced toxicity, which are known functions of BDNF. Interestingly, these effects occurred independently from BDNF receptor activation and downstream signaling, suggesting that the transfer of EV material between neurons may underlie these effects. We further observed that unlike control-stimulated EVs, BDNF-EVs do not co-localize with lysosome markers, implying that BDNF-EVs may escape lysosomal degradation. We therefore hypothesize that neuronal EVs spread messages between neurons in a regulated manner and further speculate that this may be important for synchronizing neurodevelopmental events and stress responses. Finally, we anticipate that this is relevant to several neuropsychiatric and degenerative disorders characterized by decreased BDNF signaling.