Summary: The adult brain contains millions of “silent synapses,” or immature connections between neurons that remain dormant until needed to learn new information and store new memories.
MIT neuroscientists have found that the adult brain contains millions of “silent synapses” – immature connections between neurons that remain inactive until recruited to help form new memories.
Until now, silent synapses were believed to be present only in early development, when they help the brain learn new information to which it is exposed early in life.
However, the new MIT study found that in adult mice, about 30% of all synapses in the cerebral cortex are silent.
The existence of these silent synapses may help explain how the adult brain is able to continually form new memories and learn new things without having to alter existing conventional synapses, the researchers say.
“These silent synapses seek out new connections, and when important new information is presented, the connections between the relevant neurons are strengthened. This allows the brain to create new memories without overwriting important memories stored in mature synapses, which are more difficult to modify,” says Dimitra Vardalaki, MIT graduate student and lead author of the new study.
Mark Harnett, an associate professor of brain and cognitive sciences and a fellow at MIT’s McGovern Institute for Brain Research, is lead author of the paper, which appears today in Nature.
A surprising discovery
When scientists first discovered silent synapses decades ago, they were seen primarily in the brains of young mice and other animals. During early development, these synapses are thought to help the brain acquire the massive amounts of information babies need to learn about their environment and how to interact with it.
In mice, these synapses were believed to disappear at about 12 days of age (equivalent to the first few months of human life).
However, some neuroscientists have proposed that silent synapses may persist into adulthood and aid in the formation of new memories. Evidence of this has been seen in animal models of addiction, which is thought to be largely an aberrant learning disability.
Theoretical work in the field by Stefano Fusi and Larry Abbott at Columbia University has also proposed that neurons must display a wide range of different plasticity mechanisms to explain how brains can both efficiently learn new things and retain in long-term memory.
In this scenario, some synapses must be established or changed easily, to form new memories, while others must remain much more stable, to preserve long-term memories.
In the new study, the MIT team did not look specifically for silent synapses. Instead, they were following an intriguing finding from a previous study in Harnett’s lab.
In this paper, the researchers showed that within a single neuron, dendrites — antenna-like extensions that protrude from neurons — can process synaptic input in different ways, depending on their location.
As part of this study, the researchers attempted to measure neurotransmitter receptors in different dendritic branches, to see if this would help explain the behavioral differences.
To do this, they used a technique called eMAP (epitope-preserving Magnified Analysis of the Proteome), developed by Chung. Using this technique, researchers can physically expand a tissue sample and then label specific proteins in the sample, resulting in very high resolution images.
While doing this imaging, they made a startling discovery. “The first thing we saw, which was super weird and we didn’t expect, was that there were filopodia all over the place,” Harnett says.
Filopodia, thin membrane protrusions that extend from dendrites, have been seen before, but neuroscientists weren’t sure exactly what they did. This is partly because filopodia are so small that they are difficult to see with traditional imaging techniques.
After making this observation, the MIT team set about trying to find filopodia in other parts of the adult brain, using the eMAP technique. To their surprise, they found filopodia in the mouse’s visual cortex and other parts of the brain, at a level 10 times higher than before. They also found that filopodia had receptors for neurotransmitters called NMDA receptors, but no AMPA receptors.
A typical active synapse has both of these types of receptors, which bind to the neurotransmitter glutamate. NMDA receptors normally require cooperation with AMPA receptors to transmit signals because NMDA receptors are blocked by magnesium ions at the normal resting potential of neurons.
Thus, when AMPA receptors are not present, synapses that only have NMDA receptors cannot transmit electrical current and are referred to as “silent”.
To determine whether these filopodia might be silent synapses, the researchers used a modified version of an experimental technique known as patch clamping. This allowed them to monitor the electrical activity generated at individual filopodia as they attempted to stimulate them by mimicking the release of the neurotransmitter glutamate from a nearby neuron.
Using this technique, the researchers found that glutamate would not generate any electrical signal in the filopodia receiving the input unless the NMDA receptors were experimentally unblocked. This strongly supports the theory that filopodia represent silent synapses in the brain, the researchers say.
The researchers also showed that they could “reactivate” these synapses by combining the release of glutamate with an electrical current from the body of the neuron. This combined stimulation leads to the accumulation of AMPA receptors in the silent synapse, allowing it to form a strong connection with the neighboring axon which releases glutamate.
The researchers found that it was much easier to convert silent synapses to active synapses than to modify mature synapses.
“If you start with an already functional synapse, this plasticity protocol doesn’t work,” says Harnett.
“Synapses in the adult brain have a much higher threshold, probably because you want those memories to be quite resilient. You don’t want them to be constantly squashed. Filopodia, on the other hand, can be captured to form new memories. .
“Flexible and robust”
The findings support the theory proposed by Abbott and Fusi that the adult brain includes highly plastic synapses that can be recruited to form new memories, the researchers say.
“This paper is, as far as I know, the first real evidence that this is how it actually works in the mammalian brain,” Harnett says.
“Filopodia allow a memory system to be both flexible and robust. You need flexibility to acquire new information, but you also need stability to retain important information.
Researchers are now looking for evidence of these silent synapses in human brain tissue. They also hope to study whether the number or function of these synapses is affected by factors such as aging or neurodegenerative diseases.
“It’s entirely possible that by changing the flexibility you have in a memory system, it becomes much more difficult to change your behaviors and habits or incorporate new information,” Harnett says.
“You can also imagine finding some of the molecular actors involved in filopodia and trying to manipulate some of those things to try and restore flexible memory as we age.”
Funding: The research was supported by the Boehringer Ingelheim Fund, the National Institutes of Health, the James W. and Patricia T. Poitras Fund of MIT, a Klingenstein-Simons Fellowship, a Valley Foundation Fellowship, and a McKnight Fellowship.
About this neuroscience research news
Author: Anne Trafton
Contact: Anne Trafton-MIT
Image: Image is credited to Dimitra Vardalaki and Mark Harnett
Original research: Access closed.
“Filopodia are a structural substrate for silent synapses in the adult neocortex” by Mark Harnett et al. Nature
Filopodia are a structural substrate for silent synapses in the adult neocortex
Newly generated excitatory synapses in the mammalian cortex lack sufficient AMPA-like glutamate receptors to mediate neurotransmission, resulting in functionally silent synapses that require activity-dependent plasticity to mature.
Silent synapses are abundant during early development, during which they are involved in the formation and refinement of circuits, but are thought to be rare in adulthood.
However, adults retain a capacity for neural plasticity and flexible learning which suggests that the formation of new connections is still prevalent.
Here, we used super-resolution protein imaging to visualize synaptic proteins at 2,234 synapses of layer 5 pyramidal neurons in the primary visual cortex of adult mice. Unexpectedly, approximately 25% of these synapses lack AMPA receptors.
These putative silent synapses were located at the ends of thin dendritic protrusions, called filopodia, which were an order of magnitude more abundant than previously believed (comprising about 30% of all dendritic protrusions). Physiological experiments revealed that filopodia indeed lack AMPA receptor-mediated transmission, but exhibit NMDA receptor-mediated synaptic transmission.
We further showed that functionally silent synapses on filopodia can be silenced through Hebbian plasticity, recruiting new active connections into a neuron’s input matrix.
These findings challenge the model that functional connectivity is largely fixed in the adult cortex and demonstrate a new flexible synaptic wiring control mechanism that expands the learning capabilities of the mature brain.
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