According to a study published in the March 30 issue of the journal Cell, biologists at the University of Utah have discovered that certain genes and proteins that promote growth and development of embryos also help transmit chemical signals that help individuals learn, forget, remember, and maybe even become addicted.

Senior author of the study, biology Professor Andres Villu Maricq said:

“We found that these molecules and signaling pathways [named Wnt] do not retire after development of the organism, but have a new and surprising role in the adult. They re called back to action to change the properties of the nervous system in response to experience.”

The researchers conducted the study in C. elegans – the millimeter-long roundworm or nematode. C. elegans are widely used in research as a model organism for vertebrate animals, including humans.

As studies have already demonstrated that other Wnt pathways in worms work in humans too, the researchers speculate that Wnt genes, the Wnt proteins they generate and so-called “Wnt signaling”, also play a role in human memory, learning and forgetting.

Maricq explained:

“Almost certainly what we have discovered is going on in our brain as well.” A human nicotine receptor involved in addiction, schizophrenia and some other mental disorders, is similar to a worm nerve-signal “receptor” and according to Maricq, some of the genes identified in the study “represent possible new targets for treatment of schizophrenia and perhaps addiction.”

During embryo development, Wnt genes and their proteins are known to “pattern the development and distribution of organs in the body.” In addition, when they are mutated they are responsible for developmental defects and various types of cancer.

Synapses are the connections between neurons (nerve cells) that allow electrical or chemical signals to pass to another cell. Learning and memory play a role in how synapses are produced, destroyed, strengthened or weakened. Receptors (proteins) are transferred to or removed from the synapses in order to make the connection stronger or weaker.

The researchers identified a “Wnt signaling pathway” – a series of genes and the proteins they produce – that regulates the transmission strength of a nerve signal from one neuron to another. This allows “plasticity” of synapses – a vital component in learning, remembering and forgetting.

Maricq explained:

“The adult nervous system is not a stagnant tissue, but rather dynamic and plastic, with the strength of synapses – specialized neuron-to-neuron connections – changing with experience, learning and memory. It’s not a fixed thing, like when you’re done making the heart, you’re done.”

According to Maricq, an organism learns and remembers when receptors strengthen the connection; when receptors are removed and weaken the connection, the organism forgets.

Synapses are strengthened or weakened when one neuron transmits a nerve signal and releases a chemical known as a neurotransmitter to another neuron. This neurotransmitter travels through the connection linking the two cells, and attaches to receptors on the surface of the second neuron.

Maricq said:

“You can think of the receptors like amplifiers, like hearing aids.

The volume of the received nerve signal depends on the number of receptors, which are stored in a supply depot just below the nerve cell’s surface.

The Wnt signaling identified in the new study tells the depot to put more receptors into the synapse – or not.”

Maricq highlights that the Wnt chemical signal in the study was acetylcholine and is different than the actual nerve signal transmitted by a neurotransmitter chemical.

Maricq said:

“The Wnt signal is a secondary signal that controls the volume of
the neurotransmitter signal.”

The team identified the “signaling pathway” by weakening various genes in the worms. They discovered that one neuron transmits a nerve-signal receptor called acetylcholine (ACR-16) to another neuron instructing it to increase the number of receptors on its surface, thus increasing the strength of nerve signals between the neurons.

The researchers found that when they weakened the gene that produces the ACR-16 receptor protein, there were not enough receptors, so nerve signals were disrupted and the worms “had uncoordinated movement,” according to Maricq. “They were semi-paralyzed.”

The team discovered variations of other genes that also caused weakened ACR-16 receptors and impaired the worms’ movement. They found that these genes belong to the “Wnt signaling pathway” that place a sufficient amount of receptors on the cell surface in order to receive signals.

Besides ACR-16, genes in that pathway produced proteins named CWN-2 – which is a Wnt protein – LIN-17, CAM-1 and DSH-1. How the pathway controls the strength of incoming nerve signals:

  • 1. CWN-2 is released by a neuron and attaches onto a receptor protein on the signal-receiving cell. CWN-2 is a recently discovered combination of the LIN-17 and CAM-1 proteins.

  • 2. The LIN-17/CAM-1 protein transmits a signal to a protein called disheveled (DSH-1).

  • 3. “DSH-1 somehow sends the volume-control signal that dispatches more ACR-16 receptors from depots inside the second neuron to that cell’s surface, thus boosting the volume of the received nerve signal,” said Maricq.

The team marked the ACR-16 receptors using a green jellyfish protein so they could be seen under a microscope. The researchers were able to see the green-labeled receptors gather under the surfaces of nerve cells, rather than moving to the surface, when any of the genes in the Wnt signaling pathway were mutant.

The researchers also recorded electrical currents in the synapses and discovered it was smaller when any of the genes in the Wnt signaling pathway were mutated. According to the team, this finding explains why the mutant worms were partially paralyzed.

The alpha-7 nicotinic acetylcholine receptor is the human and other vertebrates version of the ACR-16 receptor. Both receptors are similar in function and structure in animals from worms to mice, and humans.

Maricq explained:

“The alpha-7 receptor is important in schizophrenia and a number of different mental disorders, and may have a role in addiction, but we don’t understand how it’s regulated.”

There are currently many psychiatric medications that alter synapse strength. Results from the study indicate that further studies should be conducted in order to determine whether the same Wnt signaling genes in worms also control alpha-7 receptor levels on human brain cells. If this is the case, new medications might be developed to target those genes as a way to treat mental disorders, including addiction.

Maricq said:

“Addiction is like learning at a primitive level. Addiction means that somewhere in your brain, synapses are too strong. So you want more.”

Written by Grace Rattue