In early childhood, new connections form very easily in the brain. With increasing age, this high level of neural plasticity disappears in favor of long-term memories, which are stabilized by so-called perineuronal networks. Researchers have now found a way to restore neuronal plasticity in mice: To do this, they either repeatedly treated the animals with the anesthetic ketamine or with flickering light that affects the brain waves. The approach could potentially lead to strategies for treating post-traumatic stress disorder.
In the adult brain, so-called perineuronal networks stabilize the connections between the nerve cells and thus consolidate memories. The complexes of sugars and proteins accumulate around the nerve cells, dendrites and synapses and modulate the signal transmission: Existing connections are strengthened, while new ones are less easily formed. Animal experiments have shown that removing perineuronal networks increases neural plasticity and makes the brain as adaptable and capable of learning as it was in childhood.
Perineural networks dismantled
A team led by Alessandro Venturino from the Institute of Science and Technology (IST) Austria has now discovered two ways of removing perineuronal networks in mice and thus restoring the youthful plasticity of their brain: repeated treatments with the anesthetic ketamine and light flickering at a frequency of 60 Hertz .
Earlier experiments on rats had already shown that ketamine could be suitable for removing perineuronal networks. However, these were given low doses over a longer period of time – and often developed symptoms of schizophrenia as a side effect. Venturino and his colleagues, on the other hand, used such a high dose of ketamine that they put their test mice under anesthesia with it. The result: “After only three treatments we were able to determine a considerable loss of the perineuronal network, which lasted for seven days before it was rebuilt,” reports Venturino’s colleague Sandra Siegert.
Microglial activity through ketamine and light flicker
The microglia, known as immune cells of the brain, apparently play an important role in this. In a late stage of Alzheimer’s disease, these phagocytes can target synapses and nerve cells, but they can also break down the harmful plaques. “The strong reaction of the microglia to the ketamine anesthesia surprised us,” explains Venturino. “But we didn’t see any synapses or dead neurons disappear.” Instead, it turned out that the microglia eat the perineuronal network – apparently without the side effects observed in previous experiments.
Since it was already known that the microglia can also be stimulated by optical impulses, the researchers tested the extent to which the microglia activity against the perineuronal network can also be achieved without ketamine. “It has already been shown that light that flickers 40 times per second – that is, at 40 Hertz – can stimulate the microglia to remove plaques caused by Alzheimer’s disease. But the perineuronal network was not affected, ”explains Venturino. When the scientists put the mice in a box in which the light flickered 60 times per second, the effect was similar to that of the ketamine treatments.
Erasing traumatic memories
“Previous strategies for removing perineuronal networks are permanent, invasive and trigger neuropsychiatric symptoms,” the researchers explain. The high-dose ketamine treatment and the 60-hertz light flicker, on the other hand, are only minimally invasive and could therefore also open up new therapeutic approaches for humans. Once the perineuronal network in the brain has broken down, the neurons are again receptive to new input. Old synapses can be broken down more easily and new ones formed.
“But it’s not like you just take ketamine and become smart with it,” Venturino emphasizes. By restoring plasticity, one could potentially overwrite traumatic experiences and treat post-traumatic stress disorder. “But we are very careful, because something traumatic could also happen in this formative window,” warns Siegert. “It is probably also not a good idea to treat yourself with flickering light.” Further studies need to clarify which areas of application and treatments are actually promising. In addition, the scientists want to take a closer look at the molecular mechanisms behind the discovery. “There’s still a lot to research,” says Venturino.
Source: Alessandro Venturino (Institute of Science and Technology (IST) Austria, Vienna) et al., Cell Reports, doi: 10.1016 / j.celrep.2021.109313