Study begins to map the epigenetics of brain plasticity, the switch which changes neuronal function.


Scientists at the Salk Institute have discovered that the role of neurons, which are responsible for specific tasks in the brain, is much more flexible than previously believed.  By studying sensory neurons in mice, the team found that the malfunction of a single molecule can prompt the neuron to make an ‘early-career’ switch, changing a neuron originally destined to process sound or touch, for example, to instead process vision.

The team state that the finding, reported in the journal PNAS, will help neuroscientists better understand how brain architecture is molecularly encoded and how it can become miswired. It may also point to ways to prevent or treat human disorders (such as autism) that feature substantial brain structure abnormalities.

The data findings found an unexpected mechanism that provides surprising brain plasticity in maturing sensory neurons.  The mechanism, a transcription factor called Lhx2 that was inactivated in neurons, can be used to switch genes on or off to change the function of a sensory neuron in mice. It has been known that Lhx2 is present in many cell types other than in the brain and is needed by a developing fetus to build body parts. Without Lhx2, animals typically die in utero. However, it was not well known that Lhx2 also affects cells after birth.

The researchers explain that this process happens while the neuron matures and no longer divides. Previously to the current study researchers did not understand that relatively mature neurons could be reprogrammed in this way.  This data finding opens up a new understanding about how brain architecture is established and a potential therapeutic approach to altering that blueprint.

The team state that before the current study scientists had believed that programming neurons was a one-step process. They thought that the stem cells that generate the neurons also programmed their functions once they matured. While this is true, the current study found that another step is needed, the Lhx2 transcription factor in mature neurons then ultimately controls the fate of the neuron.

In the current study the scientists manipulated Lhx2 in a mouse model to make the switch in neuronal fate shortly after birth (when the mouse neurons are fully formed and considered mature). The team observed that controlling Lhx2 let them instruct neurons situated in one sensory area to process a different sense, thus enlarging one region at the expense of the other. The scientists don’t know yet if targeting Lhx2 would allow neurons to change their function throughout an organism’s life.

The results show that the brain is very plastic and that it responds to both genetic and epigenetic influences well after birth.  Clinical applications for brain disorders are a long way away, but now the medical community have a new way to think about them.

The team stress that since this study was conducted in mice, they don’t know the time frame in which Lhx2 would be operating in humans, however, the data findings show that post-birth, neurons in a baby’s brain still have not settled into their final position, they are still being wired up which can take years.

This aside, the team surmise that the findings may be an ingredient that contributes to the success of early intervention in some very young children diagnosed with autism.  This is because the brain’s wiring is determined genetically as well as influenced epigenetically by environmental influences and early intervention preventing brain miswiring may be an example of converging genetic and epigenetic mechanisms that are controlled by Lhx2.

Source:  Salk Institute for Biological Studies

 

An embryonic mouse forebrain shows the genetically modified neurons in the neocortex (orange/yellow). Cortical stem cells and neurons in other brain regions remain unaltered.  Credit:  Courtesy of Andreas Zembrzycki/Salk Institute.

An embryonic mouse forebrain shows the genetically modified neurons in the neocortex (orange/yellow). Cortical stem cells and neurons in other brain regions remain unaltered. Credit: Courtesy of Andreas Zembrzycki/Salk Institute.

 

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