Building insights on brain plasticity

31 January 2019

It is intuitive to think that anything that impedes our neurons is bad. However, the work of Dr Henry Hing Cheong Lee (Croucher Fellowship 2010), a postdoctoral fellow in the lab of Dr Takao Hensch at Boston Children’s Hospital in the US, is helping to demonstrate how neural inhibition is critical to normal brain functions and development.

Inhibition reduces how often neurons send electrochemical signals and is particularly important for controlling body movements. It can often be dysregulated in disorders such as epilepsy. “Our brains need a precise balance of excitatory and inhibitory neural signals,” Lee said.

The pace-setting researcher completed his undergraduate degree in biochemistry (2001) and master’s studies in molecular biology (2003) at Hong Kong University of Science and Technology. During his PhD studies in neuroscience (2009) at University College London and the University of Pennsylvania, Lee became interested in understanding how inhibitory signaling is controlled. He began investigating the receptor protein KCC2, important for enabling neurons to respond to inhibitory signals.

Lee discovered that high levels of a neural signaling molecule called glutamate caused KCC2 to undergo dephosphorylation, a chemical reaction, making KCC2 lose its function. As a result, neurons temporarily stopped responding to inhibitory signals

Blocking KCC2 dephosphorylation helped to reduce these effects.

Since glutamate release is associated with strokes and other types of neurological conditions, Lee’s research pointed to a possible solution for restoring the function of inhibitory neurons in such cases.

Understanding Neural Plasticity

After earning his PhD, Lee joined Dr Hensch’s lab. There, he began applying his knowledge of inhibitory neurons to studying plasticity during neural development.

There are certain “critical periods” during our lives when the nervous system undergoes rapid changes in response to environmental stimuli. At these times, neurons become highly plastic, meaning that they form many new connections that allow us to better adapt to our environment. For example, plasticity explains why children are so good at learning new things, such as languages, Lee said.

Another of these critical periods involves the development of the visual system. Neurons that express a protein called parvalbumin (PV neurons) begin sending inhibitory signals, triggering plasticity in a part of the brain called the primary visual cortex. Problems during this critical period can lead to lazy eye, where one eye loses visual acuity because the brain favours the other eye, and other conditions.

Lee is now interested in understanding how PV neurons promote the beginning of critical periods and whether these occurrences can be reopened later in life.

Exploring the Role of Otx2

Our brains need a precise balance of excitatory and inhibitory neural signals.

His curiosity was ignited by exploring whether mutations in the Otx2 gene could disrupt critical periods. Otx2 controls when PV neurons develop by binding to the perineuronal net. The net is a structure that wraps around PV neurons as they mature.

Lee and his colleagues engineered mice with a mutation in the region of Otx2 that binds to perineuronal nets. When they looked at the mice’s brains, they found that levels of Otx2 were low in the cells that had a perineuronal net. In contrast, Otx2 had accumulated in the cells without a net.

This mislocalisation of Otx2 caused fewer PV cells to develop throughout the brains of the mutant mice, delaying the critical periods for developing their visual and auditory systems. The study, published in Molecular Psychiatry in 2017, was the first to show that Otx2 regulates neural plasticity throughout the brain, not just in the visual cortex.

Connection to Mental Disorders

Neural plasticity during critical periods is hugely significant for brain development and many mental disorders are linked to problems with this process. For example, people with schizophrenia tend to have fewer PV neurons in their brains, leading to an imbalance in excitatory and inhibitory neural signaling.

Looking ahead, Lee is interested in researching whether Otx2 could be useful for reopening the critical period related to schizophrenia, allowing more PV neurons to develop.

He is also passionate about translational research, which strives to transform basic scientific discoveries into actual disease treatments. “Most molecular discoveries only end up in textbooks,” Lee said. “I’m always thinking: ‘How can we apply this knowledge to actually help people?’”

Dr Hing Cheong (Henry) Lee earned his bachelor and master’s degrees from the Hong Kong University of Science and Technology. He received his PhD from University College London in 2009 after research carried out in the lab of Dr Stephen Moss at the University of Pennsylvania. Dr Lee received a pre-doctoral fellowship from the American Epilepsy Society in 2007, as well as a post-doctoral fellowship from the American Heart Association in 2009, before receiving a Croucher Fellowship in 2010. He is currently working as a postdoctoral fellow with Dr Takao Hensch at Boston Children’s Hospital, where he is studying the role of parvalbumin neural circuits in the control of brain plasticity.

To view Dr Lee’s Croucher Profile, please click here.