Neuron Signaling Persists, Faintly, Even When Key Presynaptic Proteins Are Absent

Results from experiments in mice revise a long-held hypothesis that certain protein scaffolds are needed for synaptic activity.

By | November 1, 2016

DOCKED: Vesicles continue to release neurotransmitters into the synapse even after researchers disable docking scaffolds.© ISTOCK.COM/COSMIN4000

EDITOR'S CHOICE IN NEUROSCIENCE

The paper
S.S.H. Wang et al., “Fusion competent synaptic vesicles persist upon active zone disruption and loss of vesicle docking,” Neuron, 91:777-91, 2016.

Hair trigger
Neurons send each other signals by firing neurotransmitters across synapses. A stash of neurotransmitter-packed vesicles hunkers close to the presynaptic membrane so the vesicles can fuse with the membrane and release their cargo as soon as an electrical impulse pulls the trigger. An elaborate scaffold of proteins coordinates this vesicle docking, and scientists long assumed these proteins were essential to neuron signaling. For years, Harvard Medical School neuroscientist Pascal Kaeser has wanted “to test that very fundamental hypothesis” by “entirely [removing] that structure.”

Still talking
Kaeser and his colleagues recently got their chance. By genetically altering mice to disable key scaffolding proteins, they prevented vesicles from docking at the presynaptic membrane in cultured neurons. The results “blew us away,” Kaeser says. He expected a total shutdown of neuron signaling, yet vesicles continued to fuse with the presynaptic membrane, though much more slowly.

A simpler time
By stripping out scaffold proteins, the Harvard team might just have turned back the evolutionary clock, says Reinhard Jahn of the Max Planck Institute for Biophysical Chemistry in Germany. Neurons evolved those proteins as improvements to accelerate regular pathways for vesicle secretion, says Jahn. “Maybe we reduced a synapse to one of these more simple pathways of secretion, and that pathway still works,” Kaeser observes.

Reassembly
Defective docking sites are implicated in a range of neurological disorders, from autism to schizophrenia, Kaeser says. “If we could disrupt the entire thing, maybe we could start understanding . . . how it is put together.”

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