How to build a brain: discovery answers evolutionary mystery

May 30, 2018

Researchers at King's College London have discovered a fundamental process by which brains are built, which may have profound implications for understanding neurodevelopmental conditions like autism and epilepsy.

The study, published in Nature and funded by the Wellcome Trust, also answers an evolutionary mystery about how the delicate balance between different types of brain cells might be maintained across species with vastly different brain sizes.

The cerebral cortex is the largest region of the human brain and is responsible for many of our advanced abilities such as learning, memory and our ability to plan future actions. The cerebral cortex contains two main types of brain cells: excitatory and inhibitory neurons, which can be more simply defined as 'go' and 'no-go' neurons.

Excitatory 'go' neurons process information and provide orders telling other neurons what to do. Inhibitory 'no-go' neurons restrict the activity of excitatory neurons so that they don't all go at the same time. Too much 'go' leads to the over-firing of neurons seen in epilepsy, while too much 'no-go' causes cognitive problems.

The researchers have discovered how the correct balance is achieved in the number of 'go' and 'no-go' neurons by studying the brains of developing mice. Since the ratio of the two cell types in all mammals is remarkably similar, the findings are likely to apply to humans.

'Like many fundamental things in nature, the process we have uncovered is elegant and likely very important,' says senior author Professor Oscar Marín, from the Centre for Developmental Neurobiology at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN).

'This study fills a big gap in our understanding of how the brain is built, explaining quite simply how the balance of excitatory and inhibitory neurons in the cerebral cortex has remained constant as mammals have evolved. It is probable that this process has been critical in allowing human brains to expand.'

By manipulating brain cells in mice during a critical period of embryonic development, the researchers demonstrated that the number of 'no-go' neurons is adjusted once the number of 'go' neurons is established.

Co-lead author Dr Kinga Bercsenyi from the Marín laboratory at the IoPPN explains: 'If we imagine brain activity as a conversation, neurons have to be connected to each other in order to talk. During the first two weeks after birth, 'no-go' neurons can sense if they are alone and are programmed to die if they cannot find 'go' neurons that are willing to talk to them.'

The researchers found that 'go' neurons rescue their 'no-go' cousins from death by blocking the function of a protein called PTEN. Mutations in the gene coding for PTEN have been strongly linked to autism, suggesting that when PTEN is not functioning properly not enough 'no-go' neurons die, tipping the balance of cell types and causing problems in information processing in some autistic people.

Co-lead author Dr Fong Kuan Wong the Marín laboratory at the IoPPN says: 'As well as finding a biological process that is fundamental to brain development, our findings suggest that disruptions to this process may be fundamental to neurodevelopmental disorders. Understanding how the balance of cell types in the cerebral cortex is disrupted in conditions like autism and epilepsy could potentially lead to new treatments.'

The researchers are now investigating the consequences of having too many 'no-go' neurons in mice, and how this might relate to human conditions like autism.
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NOTES TO EDITORS

About King's College London and the Institute of Psychiatry, Psychology & Neuroscience

King's College London is one of the top 25 universities in the world (2017/18 QS World University Rankings) and among the oldest in England. King's has more than 26,500 students (of whom nearly 10,400 are graduate students) from some 150 countries worldwide, and nearly 6,900 staff. The university is in the second phase of a £1 billion redevelopment programme which is transforming its estate. http://www.kcl.ac.uk

The Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King's College London is the premier centre for mental health and related neurosciences research in Europe. It produces more highly cited publications in psychiatry and mental health than any other university in the world (Scopus, 2016), with 12 of the most highly cited scientists in this field. World-leading research from the IoPPN has made, and continues to make, an impact on how we understand, prevent and treat mental illness and other conditions that affect the brain. http://www.kcl.ac.uk/ioppn

About Wellcome

Wellcome exists to improve health for everyone by helping great ideas to thrive. We're a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations and spark debate. wellcome.ac.uk

King's College London

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