How do the faulty brain circuits involved in mental disorders such as autism or retardation develop? Researchers at Weill Cornell Medical College have helped light the way to an answer with the discovery of a mechanism that guides the wiring of neural circuits in a developing brain.
The researchers discovered that faulty wiring occurs when RNA molecules embedded in a growing axon are not degraded after they give instructions that help steer the nerve cell.
For example, the signal that tells the axon to turn — which should disappear after the turn is made — remains active, interfering with new signals meant to guide the axon in other directions.
“Understanding the basis of brain miswiring can help scientists come up with new therapies and strategies to correct the problem,” said the study’s senior author, Samie Jaffrey, M.D., Ph.D.
“The brain is quite plastic and changeable in the very young, and if we know why circuits are miswired, it may be possible to correct those pathways, allowing the brain to build new, functional wiring.”
Disorders associated with faulty neuronal circuits include epilepsy, autism, schizophrenia, mental retardation and spasticity and movement disorders, he noted.
During brain development, neurons have to connect to each other, which they do by extending their long axons to touch one another, the researchers explain. Ultimately, the neurons form a circuit between the brain and the target tissue through which chemical and electrical signals are relayed.
In the new study, researchers looked at neurons that travel up the spinal cord into the brain.
“It is very critical that axons are precisely positioned in the spinal cord,” Jaffrey said. “If they are improperly positioned, they will form the wrong connections, which can lead to signals being sent to the wrong target cells in the brain.”
The way that an axon guides and finds its proper target is through “growth cones” located at the tips of axons, he said.
“These growth cones have the ability to sense the environment, determine where the targets are and navigate toward them,” he continued. “The question has always been — how do they know how to do this? Where do the instructions come from that tell them how to find their proper target?”
The researchers found that RNA molecules embedded in the growth cone are responsible for instructing the axon to move left or right, up or down. These RNAs produce antenna-like proteins that steer the axon like a self-guided missile.
“As a circuit is being built, RNAs in the neuron’s growth cones are mostly silent,” he explained. “We found that specific RNAs are only read at precise stages in order to produce the right protein needed to steer the axon at the right time. After the protein is produced, we saw that the RNA instruction is degraded and disappears.”
“If these RNAs do not disappear when they should, the axon does not position itself properly — it may go right instead of left — and the wiring will be incorrect and the circuit may be faulty,” he continued.
The researchers didn’t anticipate that the control of brain wiring is located in these RNA molecules that are “constantly being dynamically turned over,” Jaffrey said.
“This tells us that regulating these RNA degradation pathways could have a tremendous impact on brain development,” he said. “Now we know where to look to tease apart this process when it goes awry, and to think about how we can repair it.”
The study was published in the journal Cell.
Source: Weill Cornell Medical College