We study the regulation of synaptic connectivity in the adult neocortex, a brain region affected in numerous neurodevelopmental and degenerative diseases as well as acute injuries, which are incurable to date. 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) as well as 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 investigate how this remarkable property of synapses, called synaptic plasticity, is regulated by cell-wide mechanisms and by external stimuli such as sensory experience or insults. Our aim is to understand 1) the cellular and molecular mechanisms controlling how synaptic connections are maintained, formed or lost and 2) how this knowledge can be harnessed to repair damaged neocortical circuits after injury and in human diseases, which affect axon development and maintenance, such as Down’s Syndrome and tauopathies. 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.
Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [11C]PBR28 PET brain imaging study.
Bloomfield, P. S., Selvaraj, S., Veronese, M., Rizzo, G., Bertoldo, A., Owen, D. R., Bloomfield, M. A. P., Bonoldi, I., Kalk, N., Turkheimer, F., McGuire, P., de Paola, V.*, Howes, O. D.* (2016). The American Journal of Psychiatry 173, 44-52.
Cover article | Editorial | BBC News | Imperial College London News | MRC News | New Scientist
EPBscore: a novel method for computer-assisted analysis of axonal structure and dynamics.
Song, S., Grillo, F. W., Xi, J., Ferretti, V., Gao, G., De Paola, V. (2016). Neuroinformatics 14, 121-127.
Removing synaptic breaks on learning.
Grillo, F. W., West, L., De Paola, V. (2015). Nature Neuroscience 18, 1062-1064.
In vivo single branch axotomy induces GAP-43-dependent sprouting and synaptic remodeling in cerebellar cortex.
Allegra-Mascaro, A. L., Cesare, P., Sacconi, L., Grasselli, G., Mandolesi, G., Maco, B., Knott, G., Huang, L, De Paola, V., Strata, P., Pavone, F. S. (2013). Proceedings of the National Academy of Sciences of the United States of America 110, 10824-10829.
In-vivo single neuron axotomy triggers axon regeneration to restore synaptic density in specific cortical circuits.
Canty, A. J., Huang, L., Jackson, J..S., Little, G. E., Knott, G., Maco, B., De Paola, V. (2013). Nature Communications 4, 2308.
Nature Research Highlights
Synaptic elimination and protection after minimal injury depend on cell type and their prelesion structural dynamics in the adult cerebral cortex.
Canty, A. J., Teles-Grilo Ruivo, L., Nesarajah, C., Song, S., Jackson, J. S., Little, G. E., De Paola, V. (2013). The Journal of Neuroscience 33, 10374-10383.
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Increased axonal bouton dynamics in the aging mouse cortex.
Grillo, F. W., Song, S., Teles-Grilo Ruivo, L. M., Huang, L., Ge, G., Knott, G. W., Maco, B., Ferretti, V., Thompson, D., Little, G. E., De Paola, V. (2013). Proceedings of the National Academy of Sciences of the United States of America 110, E1514-E1523.
Nature Research Highlights | F1000Prime
Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window.
Holtmaat, A.*, Bonhoeffer, T., Chow, D. K., Chuckowree, J., De Paola, V.*, Hofer, S. B., Hübener, M.*, Keck, T., Knott, G.*, Lee, W.-C. A., Mostany, R., Mrsic-Flogel, T. D., Nedivi, E.*, Portera-Cailliau, C.*, Svoboda, K., Trachtenberg, J. T.*, Wilbrecht, L. (2009). Nature Protocols 4, 1128-1144.
Except for first author, authors listed alphabetically; *Corresponding authors
Selected related publications predating the Group
Cell type-specific structural plasticity of axonal branches and boutons in the adult neocortex.
De Paola, V., Holtmaat, A., Knott, G., Song, S., Wilbrecht, L., Caroni, P., Svoboda, K. (2006). Neuron 49, 861-875.
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Diverse modes of axon elaboration in the developing neocortex.
Portera-Cailliau, C., Weimer, R. M., De Paola, V., Caroni, P., Svoboda, K. (2005). PLoS Biology 3, e272.
Nature Reviews Neuroscience Research Highlight | F1000Prime
AMPA receptors regulate dynamic equilibrium of presynaptic terminals in mature hippocampal networks.
De Paola, V., Arber, S., Caroni, P. (2003). Nature Neuroscience 6, 491-500.
Cover article | Trends in Neurosciences Research Focus
ETS gene Pea3 controls the central position and terminal arborization of specific motor neuron pools.
Livet, J., Sigrist, M., Stroebel, S., De Paola, V., Price, S. R., Henderson, C. E., Jessell, T. M., Arber, S. (2002). Neuron 35, 877-892.
Cover article | Neuron Minireview
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 (Fu et al., 2012; Yang et al., 2009), feeding behavior (Pinto et al., 2004) and metabolic homeostasis (Zeltser et al., 2012). 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) (Bayés et al., 2011). 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 awared to neuroscientists studying synaptic plasticity, with profound implications for neurological repair.
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 (in collaboration with Rick Livesey at the University of Cambridge). This approach may guide the development of new therapies to reverse cognitive impairment based on targeted synaptic intervention.
We are in London, home of one of the richest and strongest neuroscience communities in the world. We are based at the MRC London Institute of Medical Sciences (LMS), one of four institutes core-funded by the Medical Research Council (MRC) (the other being the Laboratory of Molecular Biology in Cambridge and the two newly established Francis Crick Institute and UK Dementia Research Institute in London) and part of Imperial College London, a thriving research environment with a strong expertise in neurotechnology and clinical neuroscience, and state-of-the-art facilities, equipment and technology, including super-resolution microscopy, optogenetics, genomics, next generation sequencing and automated behavioral and metabolic phenotyping. It is located on the Hammersmith Hospital Campus in London. For information on how to find us, see the Contact page.