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ABOVE: Spines in all stages of maturation—from delicate filopodia to fat-headed spines—on a dendritic branch Dimitra Vardalaki and Mark Harnett

T he information we gather throughout the course of our lives—the quickest way to get to work, for instance, or the name of a friend’s new partner—is stored in synapses. In the adult brain, new synapses are thought to be formed from scratch as needed or through the modification of existing connections. Now, a study published November 30 in Nature unearths an abundance of ready-made ‘silent synapses’ which ripen upon neuronal stimulation.

Silent synapses are otherwise complete neuronal connections that lack a key signaling protein—AMPA receptors—that renders them inactive. They were thought to be unique to early development, as previous work found that the silent connections vanish by the time a mouse has reached adulthood. But researchers may have been looking in the wrong place. In young animals, silent synapses are formed from larger protrusions called dendritic spines. But in adults, they can be found on the ends of threadlike structures called filopodia, according to the new study.

The idea to investigate filopodia was serendipitous. In a previous study, the team had used epitope-magnified analysis of the proteome (eMAP) to take super-high-resolution images of dendritic spines to investigate whether variations in neurotransmitter receptors on them accounted for differences in neuronal responses, says study coauthor Mark Harnett, a neuroscientist at MIT. During this study, they were surprised to find the branches were filled with filopodia. “There were filopodia all over the place,” says Harnett.

One of the primary ways that researchers spot synapses is by engineering mice to have fluorescent versions of their essential proteins and then looking for them using microscopy. But filopodia measure just a few hundred nanometers in diameter, so the tiny synaptic proteins on them are too tightly packed to image using standard microscopy techniques—other proteins jammed up against them block the visual signal. eMAP works by filling the cell with protein monomers like those used to absorb liquids in diapers, explains. The monomers form cross-links, embedding the proteins within a mesh which expands when a solution is added. The expansion physically separates the proteins within the tissue, rendering them visible under the microscope.

In the new study, the researchers used the technique on brain slices of the visual cortex, then on other brain regions, in mice expressing fluorescently labeled synaptic proteins. They found that the tips of filopodia were indeed covered with AMPA-deficient synapses. Without AMPA, synapses cannot be activated, as the receptors clear magnesium ions that obstruct other receptors integral to synaptic transmission.

They also realized that filopodia are far more widespread than they anticipated. They were found all over the brain and at levels ten times higher than previously described, making up 30 percent of the protrusions on a given dendritic branch. This suggests a similar proportion of synapses in the adult mouse brain are silent, waiting to be activated.

To confirm that the synapses were in fact silent, the researchers released the neurotransmitter glutamate at the tips of filopodia to mimic activity in a neighboring neuron. Unlike the synapses on dendritic spines, which responded with a burst of electrical activity, the synapses on filopodia were unresponsive. When the team washed away the magnesium ions from the same filopodium—unblocking receptors typically activated by AMPA—the silent synapse discharged a babble of electricity.

“It is a major advance to have this direct demonstration” that silent synapses are abundant in adult mice, says Yan Dong, a neuroscientist at the University of Pittsburgh who was not involved in the study. Dong’s group had previously provided potential evidence for silent synapses in cocaine-addicted adult mice: Zapping the synapses with an electrode generated no response, but when the drug was withdrawn, AMPA receptors gathered on the synapse and responded to electrical stimulation. But in such a densely packed region, the researchers could have been accidentally activating other cells, he says, so the evidence was indirect. “In neuroscience research, you believe it only when you see it,” he adds.

The researchers then went a step further, unsilencing the synapse by injecting a current into an AMPA-deficient neuron while pouring glutamate onto its filopodia. This mimics the simultaneous firing of two neurons connected by the silent synapse. After just a few rounds of stimulation, AMPA receptors accumulated on the synaptic membrane and the filopodia started to resemble a dendritic spine. Performing the same experiment on dendritic spines, however, had no effect.

The results suggest that the adult brain is far more plastic than was previously thought, says neuroscientist Gregor Schuhknecht of Harvard University, who was not involved in the study. It shows that “there’s a vast capacity for circuit remodeling,” he adds.

The study may explain how the brain is able to learn new things without having to sacrifice existing connections, the researchers say. The ability of the brain to use different synapses “solves the plasticity versus flexibility dilemma,” says Harnett. If all the brain’s synapses are flexible, then you can’t preserve old information. But if they’re all stable, then it is difficult to learn new things, he says. Instead, the brain employs both: spiny synapses for stability and filopodia for flexibility.

But instead of distinct categories, Harnett’s group are beginning to think about dendritic projections as existing on a continuum, from filopodia on one end to mature spines at the other. “It is a spectrum of maturity, strength, and plasticity,” says study author Dimitra Vardalaki, a PhD candidate in Harnett’s lab.

The researchers are now searching human brain tissue for silent synapses. They are interested in seeing whether they are as abundant as in mice, and whether their numbers change with age. “If we can figure out some of the molecular mechanisms that regulate how many filopodia there are, or how they transition into synapses, we can potentially think about treatments to bolster cognitive flexibility in old age,” says Harnett.

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