Survival of neurons in mice depends on the activity of pyramidal cells in a critical window of postnatal development, a new study from King’s College London researchers indicates. The finding represents a fundamental process by which brains are built, and may have profound implications for understanding neurodevelopmental conditions like autism and epilepsy.
The study 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. It 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. 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,"
senior author Professor Oscar Marín, from the Centre for Developmental Neurobiology at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), said.
[caption id=“attachment_95785” align=“aligncenter” width=“680”] (a) Schematic of experimental design.
(b) Total number of MGE and POA interneurons in layer 2/3 S1BF of Nkx2-1-Cre;RCLtdTomato mice (n = 3 animals per age). Data are shown as mean ± s.e.m.
(c) ROI imaged at P7 (left) and P8 (right); individual neurons numbered.
(d) Raster plots showing the occurrence of calcium events at P7 for the four numbered neurons in c.
(e) Box plots illustrating event rates for P7 interneurons that lived past P8 (magenta) and interneurons that died by P8. In box plots, the central mark indicates the median, and the bottom and top edges of the box indicate the 25th and 75th percentiles, respectively. Two-sided Mann–Whitney test, P = 0.03; n = 18 for cells that died at P8 and 153 for cells that lived beyond P8, from three pups.
(f) ROC analysis showing the ability of P7 event rates to discriminate between cells that died by P8 and cells that lived past P8. AUC (area under the curve) = 0.65, *P = 0.025. Scale bar, 15 µm.
Credit: Fong Kuan Wong, et al CC-BY[/caption]
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.
“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,"
Co-lead author Dr. Kinga Bercsenyi from the Marín laboratory at the IoPPN explained.
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.
“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,"
co-lead author Dr. Fong Kuan Wong the Marín laboratory at the IoPPN said.
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. This work was partially supported by a grant from the Wellcome Trust.
Fong Kuan Wong, Kinga Bercsenyi, Varun Sreenivasan, Adrián Portalés, Marian Fernández-Otero & Oscar Marín Pyramidal cell regulation of interneuron survival sculpts cortical networks Nature volume 557, pages 668–673 (2018)
Top Image: Computer simulated pyramidal neurons. Credit: Dr Hermann Cuntz & Prof. Michael Häusser, UCL. CC BY-NC