The root of memory: Dr Lai Kwok On studies the formation of memory
Lai is now an Assistant Professor in the School of Biomedical Sciences (Faculty of Medicine) at HKU. His research aims to understand the signal transduction mechanisms inherent in the development and functioning of neuronal synapses in order to obtain a better understanding of the cellular and molecular basis of long term memory and brain disorders such as autism.
"The brain is so much more complicated than other organs," he says. The human brain is remarkably flexible. This 'plastic' nature of the brain is attributed to the ability of neurons to change their synaptic connectivity by experience, therefore contributing to our ability to learn and form memories.
Building memories
Lai explains that when a memory is formed, the synaptic connections between relevant neurons increase in size to improve transmission efficacy. He gives the example of a child’s first encounter with a dog.
The visual memory of that animal's image is stored in a population of neurons, but the child has no idea of what the animal is called. When the parents tell the child that the animal is called a dog, the pronunciation “dog” populates a separate set of neurons.
After repetitive learning, these two populations of neurons increases their strength of connections (their synapses may become larger), and the child eventually associates the image of the dog with the pronunciation “dog”. In very simple terms, this describes memory as a change in synaptic function between neurons in the brain.
Following his MPhil and PhD degrees at HKUST under the supervision of Professor Nancy Ip, Lai was awarded a Croucher Foundation Fellowship in 2003, which enabled him to undertake postdoctoral research with Professor Kelsey Martin at UCLA in the United States. Using different optical methods to image neurons, he focused on understanding how synapses communicate with the nucleus in neurons to regulate gene expression.
Imaging neurons
Since returning to Hong Kong with his wife and two young children in 2008, Lai has adapted those imaging techniques developed at UCLA.
"In the past, very little research was being carried out in this field in Hong Kong but now it is blossoming," he says.
Lai undertakes high resolution digital imaging of live neurons. While locally activating neurotransmitters to these neurons by laser, he examines individual synapses (typically measuring about 0.5-1 micron) and observes their changes in size, shape, and number over a period up to thirty minutes in duration.
Lai explains that while transmission of information from pre-synaptic neuron to post-synaptic neuron seems simple enough, scientists now know that there are many more proteins and signal transduction machineries happening near synapses than anticipated, and they don’t understand exactly what their function is. Several hundred proteins have been identified but only a small proportion of them and their role in synaptic connections are understood.
“Even at a molecular level there are aspects of an individual neuron we don’t really understand,” he says. Importantly, the dysfunction of many of these proteins might well contribute to various brain disorders.
Brain disease
By undertaking a functional analysis of genetically mutated genes, Lai hopes to understand the cellular basis of inherited brain diseases and provide a link between genetics and cell biology.
"Autism and intellectual disability are two examples that lend themselves to this type of research. The genetic causes are heterogeneous and not caused by the mutation of a single gene," says Lai.
"Once a gene mutation has been identified, we need to understand what is happening at the cellular level in the synapses," he says.
Most excitatory synapses are present on specialized protrusions on dendrites called the dendritic spines. These structures are highly dynamic, and their development and morphology are tightly regulated by activity of the neurons. Typically, the dendritic spine holds a mushroom-like shape known as a 'mushroom spine' but in many disorders the spines are less mature and appear slimmer and finger-like, seo-called 'thin spines'.
"I am interested in understanding the molecular mechanisms by which neuronal activity control dendritic spine development and plasticity, and how these signalling pathways are disrupted in neurodevelopmental disorders such as autism and intellectual disability," says Lai.
Until recently, live imaging of gene mutations in human neurons was not possible but about four years ago, human stem cells were first differentiated into mature neurons. It remains extremely challenging, technically; but at HKU they can achieve it in a laboratory within 40-50 days.
"We can now theoretically create any disease-related mutation in human stem cells using genome editing, so we can investigate how the specific mutation affects synapse development and function in human neurons," says Lai. This development clears the path for Lai to progress his work into synaptic function and to unravel the signalling mechanisms by which neurons modulate synaptic connectivity in response to changes in neuronal activity.
Lai Kwok On is Assistant Professor in the School of Biomedical Sciences (Faculty of Medicine) at the University of Hong Kong. He received his Bachelor degree of Biochemistry from the University of Hong Kong. He was awarded a Croucher scholarship in 2000 to pursue postgraduate studies in Prof. Nancy Ip’s laboratory at the Hong Kong University of Science and Technology (HKUST). Using a combination of molecular, biochemical and cellular approaches, he studied the signal transduction mechanisms in the nervous system. In 2003,he was awarded the Croucher Foundation Fellowship, to support his postdoctoral research with Prof. Kelsey Martin at UCLA in the United States. He returned to Hong Kong in 2008 and took up his post at HKU in 2014.
To view Lai's personal Croucher profile, please click here.