A good deal gone bad: how evolving more intricate brains made us vulnerable to autism spectrum disorders

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What if the evolutionary changes which made us human also laid the foundation for some of the most complex disorders which affect us? 

Arguably, the most important feature of our species is our brain, an organ which enables us to do everything from walking and breathing to solving complex equations and reflecting on the meaning of life itself. As far as we know, no other animal has such an extensive set of skills. 

Our abilities may have something to do with the size and complexity of our brains. Brain size loosely correlates to general intelligence and improved intellectual capacities: compared to other primates, humans have the largest brains (roughly three times larger than that of chimpanzees) and the most neurons in their cortex. However, humans aren’t the biggest brained beings, by far. 

Part of the explanation lies with the timing of human development. Compared to other primates, we have long gestations and an extended childhood and adolescence. The time it takes for our brains to fully mature — some 20 years — is longer than other primates’ entire lifespans. But by extending the duration of our dependency, evolution also extended the time during which our brains are adaptable and can respond to environmental factors that shape our cognitive, emotional and social abilities. 

A major factor of our brain’s adaptability is the presence of glial cells, and in particular, oligodendrocytes. These cells of the brain and spinal cord wrap themselves around axons (long arms that neurons extend out to signal to each other) in a process known as myelination. Myelination provides axons with energetic support and allows them to transmit electrical signals faster and more robustly. This process is essential for higher executive function, and myelination is one of the ways in which the brain remains malleable throughout life. For example, several studies have linked motor learning — such as learning to juggle or play the piano — with changes to the myelination pattern in our brain. Disrupted myelination impairs brain function, as evidenced in a number of disorders such Guillain-Barré syndrome, Charcot-Marie-Tooth disease or multiple sclerosis. 

“The key to our brain’s unique capacities may not simply be its absolute or relative size, or even its number of neurons and glia, but instead more nuanced components such as increased diversity of cell types, molecular changes, and expanded or more complex patterns of neuronal connectivity,” suggest André Sousa and his colleagues from the Yale School of Medicine, reviewing the recent research into the evolution of the nervous system. However, in evolving these nuanced changes which enabled our cognitive capacities, we may also have developed a greater susceptibility to neuropsychiatric and neurological disorders.

In a paper published last month in Nature Communications, a research team led by Manno Creyghton of the Hubrecht Institute (Netherlands), found gene regulatory elements (GREs) that are unique to hominins — the group of primates that includes both humans and chimpanzees. GREs, as the name suggests, are pieces of DNA that regulate how genes are expressed in different cells. This means that even though the genes themselves remain the same, the timing and location in which they are expressed can change, causing a myriad of downstream effects. Chimpanzees are our closest genetic relatives, but you might not think from looking at them that they share 99% of our DNA. In 2015, researchers at the Stanford University School of Medicine found around 1000 GREs across the genome that were more active in one species or the other, including many involved in craniofacial development or associated with human facial variation .

Interestingly, the GREs identified by the Creyghton lab mainly affect oligodendrocytes. In fact, their study showed that the genes affected by the changes in GREs activate coincidentally with myelination. Interestingly, these genes are involved in pathways that have been linked to neurological disorders such as autism spectrum disorders (ASD). In humans, myelination begins in earnest at one or two years old, around the time when autism first becomes apparent.

Autism is known as a spectrum disorder because its symptoms vary in type and severity. These include difficulties with communication and interaction with other people, restricted interests and repetitive behaviours. Even mild forms of ASD can make day to day life challenging. To date, most researchers have investigated ASD by focusing on potential disruptions to neurons, but this study points the finger at oligodendrocytes. 

“Defects in oligodendrocyte function are gaining attention as a contributing factor to a variety of neurodegenerative and neuropsychiatric diseases,” the authors explain. “As an increased susceptibility to neural disease is unlikely to have evolved in isolation without an added benefit, connecting human evolution to neural disorders may lead to unraveling of the key genetic changes that underlie the emergence of the human brain.” In this case, studying the evolutionary changes regulating oligodendrocyte function — which differentiated us from the great apes —  may reveal new insights into the pathology of disorders such as ASD.

The story of a chance discovery, published less than three weeks later in Nature Neuroscience, adds an interesting perspective to these findings. At the Lieber Institute for Brain Development (LIBD), in Baltimore, a team led by Brady Maher were investigating a mouse model of Pitt-Hopkins syndrome, a rare developmental disorder known to produce symptoms of ASD, when they noticed something odd. “We saw a signature that suggested there might be something wrong with myelination,” said Maher. “So that was pretty surprising to us.”

The researchers then assessed other mouse models of ASD and found further evidence of a disruption to oligodendrocytes which affects their capacity to produce myelin. To test their findings in humans, the Maher lab then studied the postmortem brains of patients with common forms of ASD to assess dysregulated genes and their pathways. “It appears that in many people who suffer from ASD, their oligodendrocyte cells are not maturing sufficiently or functioning properly,” explained Maher. “This suggests that they are not producing enough myelin insulation for their neurons, which could profoundly disrupt brain development and electrical communication in the brain.” 

Though changes to myelination have been previously noted in patients with ASD, to Maher’s knowledge, this study provides the first insights into the underlying biological mechanisms. According to him, “Myelination could be a problem that ties all of these autism spectrum disorders together.” Myelination is so widespread in the brain, and controlled by so many different factors, that defects in myelination could have a variety of origins in individual cases of ASD, and may thus explain the variety of symptoms across the spectrum. 

It would appear, therefore, that as a species we made a deal with the Darwinian devil. We traded an increased likelihood of psychiatric and neurological disorders for complex, adaptable, thinking brains. In particular, evolutionary changes affecting oligodendrocytes and myelination created a greater propensity for ASD. However, “because myelination is a lifelong process, it provides a unique therapeutic opportunity that we can tap into throughout the lifespan,” explained Maher. He and his team are currently testing compounds to try to boost myelination in the brain. “Along these lines, we are eager to see whether enhancing myelination in these mice can improve their ASD-associated behaviours. Promising candidates could then be considered for clinical studies,” he added. If they succeed, they would be trialling an entirely novel treatment for autism and perhaps gain the upper hand in our evolutionary quid pro quo.

This post was written by Helena Cornu and edited by Miles Martin

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