Exosomes function in cell-cell communication during brain circuit development

Abstract

Exosomes are small extracellular vesicles that mediate intercellular signaling in the brain without requiring direct contact between cells. Although exosomes have been shown to play a role in neurological diseases and in response to nerve trauma, a role for exosome-mediated signaling in brain development and function has not yet been demonstrated. Here we review data building a case for exosome function in the brain.

Figure 1. Exosome Biogenesis

A) Exosomes may have unique cargo and signaling capacity depending on the cellular compartment of their biogenesis and release. Cartoon of a neuron with 3 compartments, dendrites, cell body and axons, boxed, from which exosomes with distinct signaling capacity could be released. B) Three possible mechanisms have been proposed for biogenesis of exosomes. The first 2 mechanisms fit the general consensus that exosome biogenesis and secretion involve multivesicular bodies (MVBs) or multivesicular endosomes (MVEs). These involve ESCRT-dependent (1) and ESCRT-independent (2) vesicle formation at MVB. In the third mechanism, observed so far only in non-neuronal cells, ESCRT-dependent vesicle formation by direct budding from the plasma membrane generates a heterogeneous population of extracellular vesicles (EVs) ranging in size from 40–1000nm. EVs in the size range of 40–110 nm label with some of the molecular markers of exosomes [12]. While EVs generated by each of these biogenetic pathways share some molecular markers, they are likely to carry different cargo and serve different functions [13,14].

Figure 2. Intercellular signaling mediated by exosomes in the nervous system

A.) Diagram of intercellular signaling mediated by exosomes between different cell types of the central and peripheral nervous systems. (a) Astrocytes stimulate neuronal arbor growth by releasing synapsin-containing exosomes [6]. (b) Mesenchimal progenitor cells seem to have similar effects by releasing and transfering microRNAs to neuronal cells[5]. (c) Microglia-derived microvesicles reportedly increase neuronal synaptic activity possibly as a homeostatic mechanism to maintain neuronal connectivity after synapse refinement or pruning[38]. In the crosstalk between neurons and microglia, exosomes derived from neurons can be collected by microglia as a mechanism for removal of toxic molecules [4]. (d) In addition, exosomes seem to play an important role in the bidirectional communication between neurons and myelinating cells (oligodenrocytes and Schwann cells) [7,36]. (e) Autocrine inhibitory exosomes derived from oligodendrocytes could play an important developmental role regulating its own expansion and the growth of the myelin sheath [10]. (f) Interneuronal signaling through exosomes has been reported under pathological conditions and may be responsible for transfer of proteins between synaptically connected cells [50,54,56]. (h) Evidence that exosomes play an important role in synaptogenesis comes from recent studies at the neuromuscular junction (NMJ), where exosomes transfer signaling molecules transynaptically which coordinate synaptic growth, maturation [–27]. B) Model hypothesizing the role for exosomes in synaptogenesis. Evi/Wg containing exosomes are released from neurons at Drosophila NMJ regulate synaptic growth and maturation [26]. Synaptotagmin 4 (Syt4) was shown to be delivered to the postsynaptic muscle via exosomes and is important for synaptogenesis through retrograde signaling from the muscle to the presynaptic motor neuron [27]. Exosomes carrying Syt4 within the vesicle lumen could fuse with the postsynaptic membrane to create a guidepost for calcium-dependent fusion of vesicles releasing a retrograde signal. SVs = synaptic vesicles; lightning bolt depicts activity.

Figure 2. Intercellular signaling mediated by exosomes in the nervous system

A.) Diagram of intercellular signaling mediated by exosomes between different cell types of the central and peripheral nervous systems. (a) Astrocytes stimulate neuronal arbor growth by releasing synapsin-containing exosomes [6]. (b) Mesenchimal progenitor cells seem to have similar effects by releasing and transfering microRNAs to neuronal cells[5]. (c) Microglia-derived microvesicles reportedly increase neuronal synaptic activity possibly as a homeostatic mechanism to maintain neuronal connectivity after synapse refinement or pruning[38]. In the crosstalk between neurons and microglia, exosomes derived from neurons can be collected by microglia as a mechanism for removal of toxic molecules [4]. (d) In addition, exosomes seem to play an important role in the bidirectional communication between neurons and myelinating cells (oligodenrocytes and Schwann cells) [7,36]. (e) Autocrine inhibitory exosomes derived from oligodendrocytes could play an important developmental role regulating its own expansion and the growth of the myelin sheath [10]. (f) Interneuronal signaling through exosomes has been reported under pathological conditions and may be responsible for transfer of proteins between synaptically connected cells [50,54,56]. (h) Evidence that exosomes play an important role in synaptogenesis comes from recent studies at the neuromuscular junction (NMJ), where exosomes transfer signaling molecules transynaptically which coordinate synaptic growth, maturation [–27]. B) Model hypothesizing the role for exosomes in synaptogenesis. Evi/Wg containing exosomes are released from neurons at Drosophila NMJ regulate synaptic growth and maturation [26]. Synaptotagmin 4 (Syt4) was shown to be delivered to the postsynaptic muscle via exosomes and is important for synaptogenesis through retrograde signaling from the muscle to the presynaptic motor neuron [27]. Exosomes carrying Syt4 within the vesicle lumen could fuse with the postsynaptic membrane to create a guidepost for calcium-dependent fusion of vesicles releasing a retrograde signal. SVs = synaptic vesicles; lightning bolt depicts activity.