New research has found that sugars affect plasticity in the brain in ways that assist in learning, memory and recovery

Can you recognise someone you haven’t seen in years, but forget what you had for breakfast yesterday?

Our brains constantly rearrange their circuitry to remember familiar faces or learn new skills, but the molecular basis of this process isn’t well understood.

Scientists now report that sulphate groups on complex sugar molecules called glycosaminoglycans (GAGs) affect ‘plasticity’ in the brains of mice.

Determining how GAGs function could help us understand how memory and learning work in humans, and provide ways to repair neural connectivity after injuries.

The sugars that sweeten fruits, sweets or cakes are actually just a few simple varieties of the many types of sugars that exist. When strung together, they can make a wide array of complex sugars.

GAGs are formed by then attaching other chemical structures, including sulphate groups.

Linda Hsieh-Wilson, of the California Institute of Technology and the project’s principal investigator, said: “If we study the chemistry of GAGs in the brain, we can learn about brain plasticity and hopefully, in the future, use this information to restore or enhance neural connections involved in memory.

“These sugars regulate numerous proteins, and their structures change during development and with disease.”



The brain’s many cells


In the brain, the most common GAG form is chondroitin sulphate, which is found throughout the extracellular matrix surrounding the brain’s many cells.

Chondroitin sulphate can also form structures known as ‘perineuronal nets’, which wrap around individual neurons and stabilise the synaptic connections between them.

One way a GAG’s function can be changed is through sulfation motifs, or patterns of sulphate groups tacked onto the sugar chains.

Hsieh-Wilson’s team is interested in how those sulfation patterns become altered, and how they might regulate biological processes such as neuroplasticity and social memory.

This could also one day allow researchers to modulate these functions as a potential treatment for central nervous system injuries, neurodegenerative diseases or psychiatric disorders.

When the team deleted the Chst11 gene responsible for forming two major sulfation patterns on chondroitin sulphate in mice, defects formed in their perineuronal nets.

However, the number of nets actually increased in the absence of the sulfation motifs, changing the types of synaptic connections between neurons.

In addition, the mice were unable to recognise mice that they had previously been introduced to, which suggests that these patterns affect social memory.

Interestingly, these nets might be more dynamic than once thought – they could be playing a role in both childhood and adulthood.

When the researchers targeted Chst11 specifically in the brains of adult mice, they found the same effects on perineuronal nets and social memory.

Hsieh-Wilson said: “That result suggests that it may be possible to manipulate these nets during adolescence or adulthood to potentially rewire or strengthen certain synaptic connections.”

In other recent experiments, the team wanted to understand how GAGs and their sulfation patterns could affect axon regeneration, or the ability of neurons to rebuild themselves after injury.

The researchers are now working to identify protein receptors that bind particular sulfation motifs.

So far, they have found that specific motifs cause these receptors to cluster together at the cell’s surface and inhibit regeneration.

This process could be blocked to create tools or treatments to promote axon regeneration.

Having more insight about this process could someday help repair damage caused by certain neurodegenerative diseases or strokes, Hsieh-Wilson says.

The researchers presented their results at the fall meeting of the American Chemical Society (ACS).

Image: Complex sugar molecules control the formation of perineuronal nets (shown here in green) that surround neurons to help stabilise connections in the brain. Credit: Linda Hsieh-Wilson’s lab.

Research Aether / Health Uncovered