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Developmental biology - Neurons

How to build a brain

Answering an evolutionary mystery about the delicate balance between types of brain cells and different brain sizes...

Researchers at King's College London have discovered a fundamental process by which brains are built, one 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 brain and is responsible for many of our advanced abilities such as learning, memory and our ability to plan future actions.

It also contains two main types of brain cells: excitatory and inhibitory neurons, simply defined hereafter 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 all do not fire 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.

Researchers have discovered how a correct balance is achieved in the number of 'go' and 'no-go' neurons by studying brains of developing mice. As the ratio of these two cell types in all mammals is remarkably similar, their findings are likely to apply to humans as well.

"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 embryo development, researchers demonstrated that the 7 'no-go' neurons are adjusted after 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."

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.
"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."

Fong Kuan Wong PhD, Marie Curie Research Fellow, Marín laboratory at the IoPPN, and co-lead author.

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.

Complex neuronal circuitries such as those found in the mammalian cerebral cortex have evolved as balanced networks of excitatory and inhibitory neurons. Although the establishment of appropriate numbers of these cells is essential for brain function and behaviour, our understanding of this fundamental process is limited. Here we show that the survival of interneurons in mice depends on the activity of pyramidal cells in a critical window of postnatal development, during which excitatory synaptic input to individual interneurons predicts their survival or death. Pyramidal cells regulate interneuron survival through the negative modulation of PTEN signalling, which effectively drives interneuron cell death during this period. Our findings indicate that activity-dependent mechanisms dynamically adjust the number of inhibitory cells in nascent local cortical circuits, ultimately establishing the appropriate proportions of excitatory and inhibitory neurons in the cerebral cortex.

Authors: Fong Kuan Wong, Kinga Bercsenyi, Varun Sreenivasan, Adrián Portalés, Marian Fernández-Otero and Oscar Marín.

We thank S. Bae for laboratory support, I. Andrew for management of mouse colonies, V. van den Berghe for help with breeding strategies, S. A. Anderson, N. Kessaris, R. L. Mort and K. A. Nave for mouse lines, N. Flames, C. Houart and M. Maravall for critical reading of the manuscript, and members of the Marín and Rico laboratories for stimulating discussions and ideas. This work was supported by a grant from the Wellcome Trust (103714MA) to O.M. F.K.W. was supported by an EMBO postdoctoral fellowship and is currently a Marie Sk?odowska-Curie Fellow from the European Commission under the H2020 Programme. K.B. is a Henry Wellcome Postdoctoral Fellow and O.M. is a Wellcome Trust Investigator.

Competing interests
The authors declare no competing interests.

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Jun 18, 2018   Fetal Timeline   Maternal Timeline   News   News Archive

Researchers at King's College London have discovered the process behind development of the cerebral cortex: that 'no-go' neurons are adjusted to the number of 'go' neurons. Image credit: public domain.

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