Scientists previously assumed that silent synapses existed only during the initial development.
Scientists at the Massachusetts Institute of Technology have discovered that the adult brain is made of millions of "silent synapses," immature connections between neurons that are not active until they are needed to make new memories.
Silent synapses were previously assumed to exist only during childhood development, aiding the brain in processing new information that was previously unknown in adult mice.
According to the researchers, the existence of these invisible synapses might aid in the development of an adult brain that is able to continually make new memories and learn new things without having to modify existing conventional synapses.
Researchers at MIT have discovered that the adult mouse brain has millions of hidden synapses, located in tiny structures called filopodia. Credit: Dimitra Vardalaki and Mark Harnett
"These silent synapses are looking for new connections, and when important new information is presented, connections between the relevant neurons are strengthened, thus the brain can create new memories without overwriting important memories stored in mature synapses, which are difficult to change," says Dimitra Vardalaki, an MIT graduate student.
Mark Harnett, an associate professor of brain and cognitive sciences, is the senior author of the paper that was recently published in the journal Nature. Kwanghun Chung, an associate professor of chemical engineering at MIT, is also a contributor.
Scientists discovered silent synapses decades ago, usually found in young mice and other animals' brains. During early development, these synapses are said to aid the brain in acquiring the necessary knowledge that babies need to grasp about their environment and how to interact with it. In mice, these synapses were predicted to vanish by about 12 days of age (equivalent to the first months of human existence).
Nonetheless, some neuroscientists have suggested that quiet synapses may be retained throughout adulthood and assist in the development of new memories. Evidence for this has been seen in animal models of addiction, which is believed to be largely a disorder of abnormal learning.
Stefano Fusi and Larry Abbott of Columbia University have also proposed that neurons must demonstrate a wide spectrum of different plasticity mechanisms to explain how brains may both efficiently learn new things and retain them in long-term memory. In this scenario, some synapses must be established or modified quickly, while others must remain substantially longer, to preserve long-term memories.
The MIT research did not aim to examine hidden synapses. Instead, they were following up on an intriguing finding from a previous investigation in Harnett's lab. Dendrites — antenna-like extensions that protrude from neurons — can process synaptic input in different ways, depending on their location.
The researchers used a technique called eMAP (epitope-preserving Magnified Analysis of the Proteome) to examine different dendritic branches' behaviors. This allows researchers to physically expand a tissue sample and label specific proteins, allowing for super-high-resolution photographs.
During the process, researchers made a surprising discovery. "The first thing we saw, which was shocking and surprising, we didn't expect," Harnett says.
Filopodia, tiny membrane protrusions that extend from dendrites, have been described previously, but neuroscientists were unable to determine what they were all about. This is partly because filopodia are so tiny that they are difficult to see using traditional imaging techniques.
The MIT team set out to discover filopodia in other areas of the adult brain, using the eMAP technique. To their surprise, they found filopodia in the mouse visual cortex and other areas of the brain, at a level 10 times higher than previously seen.
Because NMDA receptors are normally blocked by magnesium ions at the normal resting potential of neurons, a typical active synapse has both of these types of receptors. Synapses that have only NMDA receptors are termed "silent."
Researchers used a modified version of patch clamping to test whether or not these filopodia were silent synapses. This enabled them to track the electrical activity produced by individual filopodia while they attempted to stimulate them by resembling the release of glutamate from a neighboring neuron.
The researchers claim that glutamate would not generate any electrical signal in the filopodium that received the input unless the NMDA receptors were experimentally unblocked. This supports the theory that the filopodia are silent synapses within the brain.
The researchers also demonstrated that they could "unsilence" these synapses by combining glutamate release with an electrical current coming from the brain of the animal. This combined stimulation results in an accumulation of AMPA receptors in the silent synapse, enabling it to form a strong connection with the nearby axon that is releasing glutamate.
The researchers discovered that altering mature synapses was much easier than changing silent synapses.
"That plasticity protocol if you start with an already functioning synapse, it doesn't work," Harnett says. "You want those memories to be pretty resilient, but you don't want them to be constantly overwritten." Filopodia, on the other hand, can be captured to create new memories.
The findings support Abbott and Fusi's claim that the adult brain contains highly flexible synapses that may be recruited to create new memories.
"This is the first true investigation that this is how it actually works in a mammalian brain," Harnett says. "You need flexibility to acquire new information, but you also need stability to maintain important information."
Researchers are now looking for evidence of these hidden synapses in human brain tissue. They hope to also investigate whether or not factors such as age or neurodegenerative disease affect their functioning.
“It's entirely possible that changing the amount of flexibility you've got in a memory system will make it much harder to change your behaviors and habits or incorporate new information,” Harnett says. “You might also try manipulating some of those things to reclaim flexible memory as we age.”
Dimitra Vardalaki, Kwanghun Chung, and Mark T. Harnett, Nature, 30 November 2022, DOI: 10.1038/s41586-022-05483-6
The study was funded by the Boehringer Ingelheim Foundation, the National Institutes of Health, the James W. and Patricia T. Poitras Fund at MIT, a Klingenstein-Simons Fellowship, a Vallee Foundation Scholarship, and a McKnight Scholarship.