La synapse st une zone de contact fonctionnelle qui s’établit entre deux neurones, ou entre un neurone et une autre cellule (cellules musculaires, récepteurs sensoriels…). Elle assure la conversion d’un potentiel d’action déclenché dans le neurone présynaptique en un signal dans la cellule postsynaptique. On estime, pour certains types cellulaires (par exemple cellule pyramidale, cellule de Purkinje…), qu’environ 40 % de la surface membranaire est couverte de synapses. Wikipedia
Intervenir dans le cerveau pour modifier les transmissions d’influx nerveux est une opération a risque. Elle peut entrainer la destruction de plus vastes zones du cortex superficiel, entraient des paralysies ou des hallucinations. On cite notamment l’obsessive compulsive disorder (OCD) Néanmoins l’intervention sera de plus en plus tentée en cas par exemple de tumeur ou de chocs violents entraînant des destructions locales du cortex.
Aussi, à la Duke University de Durham (Etats-Unis) la décision a-t-elle été prise de faire de premières expériences chez des souris. Leur cerveau est bien plus petit que celui de l’homme, comme nul n’en ignore, mais il s’agit de mammifères proches de l’homme en ce qui concerne les grandes fonctions cérébrales.
On distingue les synapses au microscope électronique par la taille de la fente synaptique ; de l’ordre de 2 nanomètres pour les synapses électriques, entre 10 et 40 nm pour les synapses chimiques. On peut également, dans le cas des synapses électriques, observer les jonctions communicantes. Au niveau d’une synapse, il s’agit toujours d’un contact entre deux membranes plasmiques, il n’y a jamais fusion en un syncytium.
Les chercheurs cherchaient à savoir si des synapses électriques artificielles pouvaient remplacer les signaux chimiques des synapses naturelles. Un travail analogue avait été fait en utilisant des vers dits nématodes mais le cerveau de ceuc-ci, si cerveau il y a, ne comporte que 300 neurones tandis que la souris en a 71 millions.
Ils implantèrent ensuite des connexines dans le cerveau des souris. Les connexines constituent une grande famille de protéines transmembranaires qui permettent la communication intercellulaire et le transfert d’ions et de petites molécules de signalisation entre les cellules .. Ces connexisnes provenaient d’un poisson …
Note Retour à l’article en anglais, non traduit ici faute de temps
called the white perch (Morone americana). These connexins would later be used by the nerve cells on either side of the junction at the synapse, like the positive and negative parts of a circuit.
After identifying the right proteins, the next issue was knowing where to place them. “We implanted lots of electrodes about the size of a hair into many brain areas at the same time in mice and then we recorded their electrical activity,” says Dzirasa. “This gives an electrical map of how information is flowing through the brain.”
The team then exposed the mice to situations that induce behaviours like anxiety or aggression to see how this flow changed, pinpointing which brain cells should receive the engineered synapse.
Once these had been identified, the researchers injected a harmless virus into the mice’s brains to deliver the genetic information needed to make the connexins. This resulted in working electrical synapses that changed how electricity moved in a microcircuit in the frontal cortex. The mice then showed signs of being more explorative and sociable, suggesting this approach could help treat conditions like social anxiety.
“It’s a cute idea,” says David Spray at the Albert Einstein College of Medicine in New York. “It will likely provide a useful tool to answer the question of what would happen to activity patterns and behaviours if we added electrical synapses to specified cell types in neural circuits.”
The researchers also did a further experiment investigating the potential of this technique for preventing mental health issues. “We wanted to know if we could use this tool to promote resilience,” says Dzirasa.
To attempt this, Dzirasa and his colleagues targeted a long-range circuit between the frontal cortex and an area of the brain called the thalamus. They identified this circuit as important when mice are stressed, which is a sensation they may respond to by freezing in place. Introducing the engineered electrical synapses enhanced communication between these regions and stopped the mice from freezing.
“We have created an approach to edit the connection between cells, enabling targeted rewiring of the brain,” says Dzirasa. “It has the potential to edit many different types of genetically inducted wiring deficits to prevent the emergency of psychiatric disorders.”
Katrin Amunts at the Jülich Research Centre in Germany says that while the research is at an early stage, the scientists “demonstrate in the mouse model that a targeted change at the subcellular level can have an effect at the behavioural level, so there is psychiatric relevance”.
Further work by Dzirasa and a different group of colleagues introduced connexins into juvenile mice genetically predisposed to develop OCD-like symptoms. “Normally, over time, the mice start grooming a lot, and the grooming can be so severe that they get these huge facial lesions that mirror the lesions that some people with OCD get when they compulsively wash their hands,” says Dzirasa.
The mice with the electrical synapses groomed less and about two-thirds of them never developed facial lesions, he says.
Despite the work being done in mice, Dzirasa selected connexins 34.7 and 35 partly on the basis that they should work similarly in people. Existing atlases of gene expression profiles in humans could also identify which cells to target.
“These gene expression patterns are like a GPS indicator,” he says, showing which cells do what. Viruses carrying the necessary genomic material could be injected into the bloodstream and then pass through the blood-brain barrier, which could also be opened via focused ultrasound, to target cells with the right profiles, says Dzirasa.
“I’m personally very excited,” says Ithai Rabinowitch at the Hebrew University of Jerusalem in Israel, part of the team that put an electrical synapse in C. elegans. “Engineering or editing synaptic connections provides a potential all-biological approach for elucidating neural circuit function and for potentially treating various diseases involving neural connectivity,” he says. “Importantly, once installed, these new connections drive neural circuit information flow and function completely autonomously, with no need for external activation or regulation.”
But brain editing in people is a long way off and raises ethical questions, says Dzirasa. “I just want to make sure there’s something available for people if they need it.”
Rabinowitch also wonders if the brain would respond to the changes by making new neural links that may undo the effects of the engineered synapses or create other potentially negative pathways. The intervention might also have unknown side effects, he says.
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Reference:
bioRxiv DOI: 10.1101/2025.03.25.645291
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