Clinical Neuroscience

The brain’s Twitter system: Neuronal extracellular vesicles

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Twitter, a microblogging and social networking service, has become a “go-to’” for conversations, updates, breaking news, and sharing the more mundane aspects of our lives. Tweets, which were lengthened from 140 to 280 characters in 2017, rapidly communicate and disseminate information to a wide audience. Generally, tweets are visible to everyone, though users can mute and block other users from viewing their tweets. Spikes in tweets and tweeting frequency reflect hyper-current events: the last minutes of the Super Bowl, certification of an election, or a new movie release. In fact, social scientists have analyzed tweet frequencies to examine the impact of local and national events. However, few are aware that like celebrities, politicians, influencers, and ordinary citizens, the human brain also tweets.

In this article, we describe the components of the brain’s “Twitter” system, how it works, and how it might someday be used to improve the diagnosis and treatment of psychiatric disorders.

Brain tweets

The brain’s Twitter system involves extracellular vesicles (EVs), tiny (<1 µm) membrane-bound vesicles that are released from neurons, glia, and other neuronal cells (Table). These EVs cross the blood-brain barrier and facilitate cell-to-cell communication within and among tissues (Figure 1).

Neuronal cells that release extracellular vesicles

First described in the 1980s,1 EVs are secreted by a diverse array of cells: mast cells reticulocytes, epithelial cells, immune cells, neurons, glia, and oligodendrocytes. Like tweets, EVs rapidly disseminate packets of information throughout the brain and body and direct the molecular activity of recipient cells in both health and disease. These “brain tweets” contain short, circumscribed messages, and the characters are the EV cargos: RNAs, proteins, lipids, and metabolites. Like a Twitter feed, EVs cast a wide communication net across the body, much of which finds its way to the blood. As neuroscientists, we can follow these tweets by isolating tissue-derived EVs in plasma and examining their surface molecules and cargo. By following this Twitter feed, we can tap into important molecular communications and identify “trending” (evolving) pathological processes, and perhaps use the brain Twitter feed to improve diagnosis and treatments. We can pinpoint, in the blood, signals from CNS processes, down to the level of identifying EV cargos from specific brain cell types.

Extracellular vesicles

Within the CNS, EVs are secreted by neurons, where they may modulate synaptic plasticity and transfer molecular cargo among neurons. EVs also facilitate communication between neurons and glia, maintain homeostasis, trigger neuroprotective processes, and even regulate synaptic transmission.2

What’s in a brain tweet?

To discuss what’s in a brain tweet, we must first understand how a brain tweet is composed. EVs are pinched off from membranes of intercellular structures (eg, golgi or endoplasmic reticulum) or pinched off directly from cell membranes, where upon release they become EVs. There is a complex cellular machinery that transports what ultimately becomes an EV to the cell membrane.3 EVs contain unique mixtures of lipids, proteins, and nucleic acids (eg, microRNA [miRNA], mRNA, and noncoding RNA).4 To date, nearly 10,000 proteins, 11,000 lipids, 3,500 mRNAs, and 3,000 miRNAs have been identified as cargos in extracellular vesicles (Figure 1). Similar to how the release of EVs is dependent on complex intracellular machinery, the packing of these contents into what will become the EV involves a parallel set of complex machinery that is largely directed by endosomal sorting complexes required for transport (ESCRT) proteins.5 Of interest, when viruses attack cells, they hijack this EV packaging system to package and release new viruses. EVs vary in size, shape, and density; this variation is related to the cell origin, among other things. EVs also differ in their membrane lipid composition and in terms of transmembrane proteins as well as the proteins that facilitate EV binding to target cells (Figure 2).6 Ultimately, these exosomes are taken up by the recipient cells.

Extracellular vesicle communication mechanisms

EV-facilitated neuron-to-neuron tweets have been implicated in neuronal growth and differentiation.7 EV-driven communication between cells also can decrease dendrite growth and can trigger microglia to prune synapses.8 EVs from glial cells may promote neuronal integrity, directly boost presynaptic glutamate release,9 or even, through miRNAs, change the expression of glutamate receptors.10 EVs from astrocytes transport proteins that enable neuronal repair, while EVs from microglia regulate neuronal homeostasis. EV cargos—lipids, proteins, and miRNAs—from neurons modify signal transduction and protein expression in recipient cells. Taken together, data suggest that EVs facilitate anterograde and retrograde transfer of signals across synapses,7,11 a putative mechanism for driving synaptic plasticity,12 which is a process implicated in the therapeutic efficacy of psychotropic medications and psychotherapies.

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