How connections in the brain change over time
A research team led by Dr Lai Kwok-On (Croucher Fellowship 2003), at the University of Hong Kong (HKU), has uncovered the molecular basis of how neurons change their connections during brain development.
The findings may have important implications not only in understanding the developing brain but also neurodegeneration of the nervous system.
Neurons communicate with each other in the brain through neurotransmitters, which exert their actions at a specialised connection between two neurons known as a dendritic spine.
During their initial formation, dendritic spines are elongated and motile, which helps neurons find and connect to their partners. As the brain matures, these junctions need to be refined and become more stable by changing to a mushroom-shaped morphology.
The switch from elongated to mushroom spine is important for brain function, but the molecular mechanism underlying this transition is not fully understood.
Lai, an Assistant Professor at the School of Biomedical Sciences in the Faculty of Medicine at HKU, and his researchers have now discovered that an enzyme known as PRMT8 is pivotal for determining the shape of dendritic spines.
The enzyme modifies the function of its target protein by the addition of a methyl group. This type of protein modification is known to be prevalent in nuclei to control DNA and gene expression. However, the research team found little PRMT8 present in the nucleus of a neuron. Instead, the enzyme was located in the dendritic spine.
As the brain matures, PRMT8 becomes more abundant. By preventing the synthesis of PRMT8 in neurons, Lai and colleagues discovered the enzyme restrains the formation of elongated spines.
Dendritic spines are rich in the protein, actin, which forms a polymer and acts like a treadmill in driving the dynamic change of neuronal connections. The team found that PRMT8 was able to indirectly control the treadmill activity of actin via methylation of an RNA-binding protein, ultimately shifting the elongated spines to mushroom-shaped in the mature brain.
In addition, and surprisingly, when PRMT8 was deficient, mice models became less anxious in two different animal behavioural tasks.
The findings uncovered a new mechanism by which neuronal connections are refined during brain development.
The discovery may also facilitate our understanding of neurodegenerative diseases, given the increasing evidence that suggests protein methylation and RNA metabolism become abnormal in neurons affected by amyotrophic lateral sclerosis and frontotemporal dementia.
The study has been published in the journal Cell Reports.
“The next important question to address is whether early neurodegeneration that changes brain connectivity before neuronal death involves perturbation of PRMT8 activity and its target RNA-binding proteins,” Lai said.
Dr Lai Kwok-On received his Bachelor of Biochemistry from the University of Hong Kong. He pursued postgraduate studies at the Hong Kong University of Science and Technology. With the help of his Croucher Foundation Fellowship, he then undertook postdoctoral research at the University of California, Los Angeles, in the United States. He is now an Assistant Professor in the School of Biomedical Sciences, Faculty of Medicine, at the University of Hong Kong. Dr Lai received his Croucher Fellowship in 2003.
To view Dr Lai’s Croucher profile, please click here.