The focus of our work
Our underlying focus is on understanding the fundamental principles of synaptic development and plasticity in the living brain. Nerve connections, termed synapses (from the Greek ‘to clasp’) by Nobel laureate Charles Sherrington in 1897 (see Burke, 2007), are the points of contact between neurons where information is exchanged. The history of how the existence of synapses was first postulated and then proved is a fascinating one, spanning almost a century. Pioneering work in reduced preparations (e.g. from N. Ziv and C. Garner), model organisms such as Xenopus (H. Cline), Drosophila (G. Davis), zebrafish (S. Smith) and Caenorhabditis elegans (K. Shen) have contributed a great deal to our understanding of how synapses develop and mature. In mammals, due to technical limitations, the smaller and less accessible synapses of the brain have been less studied compared to large synapses such as the neuromuscular junction in the periphery, the Calyx of Held in the brainstem and the ribbon synapse in the retina (Sanes and Lichtman, 2001). More recently, using revolutionary microscopy methods such as multiphoton microscopy (Denk et al., 1990), we and others have discovered that synapses are continuously replaced even in the mature brain (Hübener and Bonhoeffer, 2010; Holtmaat and Caroni, 2016). These synaptic changes underlie cognitive processes such as learning and memory (Bailey, Kandel et al., 2015). Synapses are therefore structurally ‘changeable’ or ‘plastic’ in the adult brain, and this fundamental property is widely believed to be a key element of information storage and retrieval in the brain.
We study the regulation of synaptic connectivity in the mammalian neocortex.
Our research revolves around understanding the regulation of cortical circuit connectivity and function and its relevance for both neurodevelopmental and neurodegenerative disease processes in the brain. We aim to understand
- the cellular and molecular mechanisms controlling the life cycle of synaptic connections (e.g. their formation, maintenance, elimination and regeneration), and
- how this knowledge can be harnessed to help design new treatment strategies for the numerous diseases affecting synapses, collectively called synaptopathies.
Some basic questions we are addressing are:
- What are the principles controlling synapse formation and degeneration, and how can experience, ageing, damage or disease change them?
- Which intracellular signalling pathways underlie the stability or modification of neuronal circuits and how can they be manipulated to design new therapies for neurological diseases?
- How can we unravel human-specific features of synaptic development, plasticity and degeneration in diseases?
Despite the fundamental nature of these questions we are far from a complete understanding of the regulation of synaptic connectivity in the brain. Our program is focused on tackling these questions in order to better capture the synaptic basis of cognitive function and impairment.
To guide the development of more effective therapies for a range of neurocognitive disorders
We believe a deeper understanding of the mechanisms regulating synaptic connectivity is ultimately important to guide the development of more effective therapies for a range of neurocognitive disorders, including acute injury and neurodegeneration, as well as to enhance the brain regenerative potential.
Synapses play a pivotal role in brain function. The degree of synaptic rearrangement in the brain affects cognitive functions, including learning and memory, feeding behavior and metabolic homeostasis. It is becoming increasingly clear that numerous diseases, including neuropsychiatric and metabolic conditions, primarily target the synapse. For example, no other set of proteins in the nervous system carries a greater disease burden than synaptic proteins (e.g., mutations in synaptic proteins cause more than 130 diseases). As opposed to cell death, synaptic structural alterations, including overproduction, loss or instability, and axon degeneration are associated with the appearance of cognitive symptoms in many of these diseases.
Synaptic biology is therefore a major theme in neuroscience. In 2013, the Albert Lasker Basic Medical Research Award and the Nobel Prize in Physiology or Medicine were awarded for studies on synaptic transmission, and the 2015 and 2016 Brain Prizes and the 2016 Kavil Prize in Neuroscience were awarded to neuroscientists studying synaptic plasticity, with profound implications for neurological repair.
A multidisciplinary approach
We use a multidisciplinary approach, combining molecular genetic and behavioral studies with a variety of advanced neuroimaging techniques such as correlative in vivo 2-photon-electron microscopy, calcium and super-resolution imaging, pharmaco/opto-genetics and MR/PET imaging (in collaboration with Oliver Howes at Imperial College London and King’s College London) and with organotypic in vitro assays to gain mechanistic and functional insights. Specifically, we are trying to understand basic principles of synaptic development and plasticity by visualizing and manipulating both rodent and, more recently, human cortical circuits directly in the living brain. This approach may guide the development of new therapies to reverse cognitive impairment based on targeted synaptic intervention.
Our work would not be possible without the generosity of the support from Imperial College London, the Medical Research Council (MRC), the EU Horizon 2020, Alzheimer’s Research UK (ARUK), the Engineering and Physical Science Research Council (EPSRC) and Rosetrees Trust.
A vibrant neuroscience community
We are based in Singapore (National University of Singapore) and London (Imperial College London), home of some of the richest and strongest neuroscience communities in the world. In Singapore, we are in the Signature Research Programme in Neuroscience and Behavioural Disorders at Duke-NUS Medical School, which has strong preclinical and clinical research, and expertise in human stem cell biology, genetics, behaviour and organotypic models of human disease. In London, we are based at the Department of Brain Sciences of Imperial College London, a thriving research environment with strengths in , neurodegeneration and , and , including , optogenetics, , next-generation DNA sequencing and automated behavioural and metabolic phenotyping. We also have ties to the and , two of four institutes core-funded by the (the others being the in Cambridge and the in London) and part of . For information on how to find us, please click here for Singapore and here for London.Contact Us