Electrical synapses that carry messages through the brain have been artificially engineered in mammals for the first time, altering their behaviour. This could have potential for preventing or treating a range of mental health conditions, including obsessive compulsive disorder (OCD).
Connections, or synapses, between nerve cells are either electrical or chemical. Chemical ones, which are more common in mammals, involve molecules called neurotransmitters, whereas electrical synapses rely on proteins called connexins.
Many mental health conditions seem to occur when something goes wrong with the neurotransmitter-based signalling system, says at Duke University in Durham, North Carolina. 鈥淲e wanted to know if we could engineer a way to bypass the chemical synapses between cells by putting an electrical synapse there.鈥�
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First, Dzirasa and his colleagues looked for proteins from other organisms that could be used to build an electrical synapse in mice. Similar work was previously done in the nematode worm Caenorhabditis elegans, but that animal only has 302 neurons, so it was relatively simple, whereas mice have about 71 million neurons.
鈥淲e found [the connexins] by searching an incredible amount of literature to find proteins with exactly the properties that we鈥檇 want to engineer a human system with,鈥� says Dzirasa.
They opted for connexins called 34.7 and 35, found in a fish 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. 鈥淲e 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,鈥� says Dzirasa. 鈥淭his gives an electrical map of how information is flowing through the brain.鈥�
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鈥檚 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.
鈥淚t鈥檚 a cute idea,鈥� says at the Albert Einstein College of Medicine in New York. 鈥淚t 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.鈥�
The researchers also did a further experiment investigating the potential of this technique for preventing mental health issues. 鈥淲e wanted to know if we could use this tool to promote resilience,鈥� 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.
鈥淲e have created an approach to edit the connection between cells, enabling targeted rewiring of the brain,鈥� says Dzirasa. 鈥淚t has the potential to edit many different types of genetically inducted wiring deficits to prevent the emergency of psychiatric disorders.鈥�
at the J眉lich Research Centre in Germany says that while the research is at an early stage, the scientists 鈥渄emonstrate 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鈥�.
Further work by Dzirasa and a different group of colleagues introduced connexins into juvenile mice genetically predisposed to develop OCD-like symptoms. 鈥淣ormally, 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,鈥� 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.
鈥淭hese gene expression patterns are like a GPS indicator,鈥� 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.
鈥淚鈥檓 personally very excited,鈥� says at the Hebrew University of Jerusalem in Israel, part of the team that put an electrical synapse in C. elegans. 鈥淓ngineering or editing synaptic connections provides a potential all-biological approach for elucidating neural circuit function and for potentially treating various diseases involving neural connectivity,鈥� he says. 鈥淚mportantly, once installed, these new connections drive neural circuit information flow and function completely autonomously, with no need for external activation or regulation.鈥�
But brain editing in people is a long way off and raises ethical questions, says Dzirasa. 鈥淚 just want to make sure there鈥檚 something available for people if they need it.鈥�
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.
bioRxiv
bioRxiv
