The role of Wnt signalling in synaptic maintenance
Lead Research Organisation:
University College London
Department Name: Cell and Developmental Biology
Abstract
The formation of functional synapses, points of contact between two nerve cells (neurons) is crucial for proper brain function. Synapses are very dynamic structures that grow, shrink and change shape through the entire life of the organism. A dialogue between the pre-synaptic neuron (neurotransmitter releasing cell) and its postsynaptic target (a neurotransmitter responding cell) is essential for the formation, growth and maintenance of synapses. Importantly, the formation of new synapses and the remodelling of old ones underlay important functions such as learning and memory. Moreover, recent studies suggest that synaptic loss precedes the death of neurons observed in several neurodegenerative diseases. However, little is known about how synapses are maintained or protected against injury.
Our laboratory has been studying the function of secreted factors, called Wnts, in the maintenance of synapses. We found that Wnt blockade induces the loss of mature synapses indicating that Wnts are critical for their maintenance. In this grant proposal, we will examine the molecular mechanism by which Wnts regulate synaptic maintenance and how this process influences neuronal connectivity and animal behaviour. Our results could contribute to the development of therapeutic strategies for the treatment of diseases in which synapses are compromised.
Our laboratory has been studying the function of secreted factors, called Wnts, in the maintenance of synapses. We found that Wnt blockade induces the loss of mature synapses indicating that Wnts are critical for their maintenance. In this grant proposal, we will examine the molecular mechanism by which Wnts regulate synaptic maintenance and how this process influences neuronal connectivity and animal behaviour. Our results could contribute to the development of therapeutic strategies for the treatment of diseases in which synapses are compromised.
Technical Summary
Understanding the molecular mechanisms that regulate the formation, maintenance and function of synapses has been central for developing therapeutic approaches for the treatment of neurological conditions, nerve and brain injury as well as neurodegenerative diseases.
In the last two decades a considerable progress has been made in the elucidation of the molecular mechanisms that control the formation of neuronal circuits. Our laboratory made a significant contribution to this field with the discovery that Wnt proteins regulate neuronal connectivity by inducing the formation of synapses in the central nervous system.
More recently we found that Wnt signaling is also required for the maintenance of mature synapses. We found that Wnt blockade by Dkk1, a Wnt antagonist that specifically blocks canonical Wnt signalling, induces the disassembly of mature synapses in cultured neurons. We also found that Wnt signalling specifically regulates excitatory synapses. In this grant proposal we are taking an interdisciplinary approach to elucidate the function of Wnt signalling in synaptic maintenance, its mechanism and its contribution to animal behaviour. We will examine:
1) The role of Wnt signalling on synaptic maintenance. The effect of loss of Wnt function or Wnt blockage on the maintenance of synapses will be examined in hippocampal cultures and in the brain. Inducible transgenic expressing Dkk1 and the conditional Wnt7b mutant mice, in which Wnt signalling is specifically affected in the adult hippocampus, will be analysed. A combination of immunofluorescence approaches, electron microscopy and live cell imaging techniques will be used to establish the cellular steps leading to the disassembly of synapses upon the loss of Wnt signalling.
2) The signalling transduction pathways involved in Wnt-mediated synaptic maintenance. For this purpose, we will specifically examine the role of the canonical Wnt signalling pathway using gain and loss of function approaches. These studies will contribute to further elucidate the mechanisms that govern synaptic assembly and disassembly.
3) The contribution of Wnt signalling in synaptic transmission and plasticity in mature neurons. We will specifically examine the function of Wnt signalling in the maintenance of the proper ratio of excitatory to inhibitory synapses, and of silent synapses. Furthermore, we will test whether Wnt signalling regulates LTP and LTD in the hippocampus.
4) The function of Wnt signalling on the behaviour of young adult mice by analysing inducible transgenic mice expressing Dkk1 and conditional Wnt7b mutant mice.
In the last two decades a considerable progress has been made in the elucidation of the molecular mechanisms that control the formation of neuronal circuits. Our laboratory made a significant contribution to this field with the discovery that Wnt proteins regulate neuronal connectivity by inducing the formation of synapses in the central nervous system.
More recently we found that Wnt signaling is also required for the maintenance of mature synapses. We found that Wnt blockade by Dkk1, a Wnt antagonist that specifically blocks canonical Wnt signalling, induces the disassembly of mature synapses in cultured neurons. We also found that Wnt signalling specifically regulates excitatory synapses. In this grant proposal we are taking an interdisciplinary approach to elucidate the function of Wnt signalling in synaptic maintenance, its mechanism and its contribution to animal behaviour. We will examine:
1) The role of Wnt signalling on synaptic maintenance. The effect of loss of Wnt function or Wnt blockage on the maintenance of synapses will be examined in hippocampal cultures and in the brain. Inducible transgenic expressing Dkk1 and the conditional Wnt7b mutant mice, in which Wnt signalling is specifically affected in the adult hippocampus, will be analysed. A combination of immunofluorescence approaches, electron microscopy and live cell imaging techniques will be used to establish the cellular steps leading to the disassembly of synapses upon the loss of Wnt signalling.
2) The signalling transduction pathways involved in Wnt-mediated synaptic maintenance. For this purpose, we will specifically examine the role of the canonical Wnt signalling pathway using gain and loss of function approaches. These studies will contribute to further elucidate the mechanisms that govern synaptic assembly and disassembly.
3) The contribution of Wnt signalling in synaptic transmission and plasticity in mature neurons. We will specifically examine the function of Wnt signalling in the maintenance of the proper ratio of excitatory to inhibitory synapses, and of silent synapses. Furthermore, we will test whether Wnt signalling regulates LTP and LTD in the hippocampus.
4) The function of Wnt signalling on the behaviour of young adult mice by analysing inducible transgenic mice expressing Dkk1 and conditional Wnt7b mutant mice.
Publications

Ciani L
(2015)
Wnt signalling tunes neurotransmitter release by directly targeting Synaptotagmin-1.
in Nature communications

Dickins EM
(2013)
Wnts in action: from synapse formation to synaptic maintenance.
in Frontiers in cellular neuroscience

Galli S
(2014)
Deficient Wnt signalling triggers striatal synaptic degeneration and impaired motor behaviour in adult mice.
in Nature communications

Hiester BG
(2013)
Neurotrophin and Wnt signaling cooperatively regulate dendritic spine formation.
in Molecular and cellular neurosciences

Jolly S
(2019)
Single-Cell Quantification of mRNA Expression in The Human Brain.
in Scientific reports

Marzo A
(2016)
Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus.
in Current biology : CB

McLeod F
(2017)
Evaluation of Synapse Density in Hippocampal Rodent Brain Slices.
in Journal of visualized experiments : JoVE

McLeod F
(2018)
Wnt Signaling Mediates LTP-Dependent Spine Plasticity and AMPAR Localization through Frizzled-7 Receptors.
in Cell reports

Purro SA
(2014)
Dysfunction of Wnt signaling and synaptic disassembly in neurodegenerative diseases.
in Journal of molecular cell biology

Stamatakou E
(2015)
Wnt Signalling Promotes Actin Dynamics during Axon Remodelling through the Actin-Binding Protein Eps8.
in PloS one
Description | Defining the role of Wnt-Fz7 signalling in long-term plasticity in health and disease |
Amount | £681,001 (GBP) |
Funding ID | MR/S012125/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2019 |
End | 02/2023 |
Description | Collaboration with Professor Alasdair Gibb from UCL |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are conducted experiments to address the impact of Wnt signalling in synaptic connectivity |
Collaborator Contribution | Our Collaborator Prof Gibb provided advice on the design and analyses of electrophysiological studies |
Impact | research publications |
Start Year | 2015 |
Description | Collaboration with the ARUK DDI at UCL |
Organisation | Alzheimer's Research UK |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | We are planning to test compounds that could activate Wnt signalling with the view to ameliorate or restore synapse degeneration. |
Collaborator Contribution | ARUK will provide a range of compounds to do a screen. |
Impact | No outcomes yet |
Start Year | 2017 |
Description | The role of Wnt signaling in synaptic connectivity |
Organisation | University College London |
Department | Neuroscience, Physiology & Pharmacology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Prof. Alasdair Gibb has been our long-term collaborator. He is expert electrophysiologist who guides my PhD students and postdoc in the use of different electrophysiological techniques |
Collaborator Contribution | We have published a number of papers together. |
Impact | This is a multi-disciplinary collaboration. |
Start Year | 2011 |
Description | BBC World Service |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I was invited to discuss our recent findings on the link between Dkk1 and Alzheimer's disease at the BBC World Service. Increased awareness of the importance of fundamental research in medicine. |
Year(s) Of Engagement Activity | 2012 |
Description | Interview by Alzheimer Research Forum (Alzforum) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | Telephone and email correspondence regarding an important publication in the field of Alzheimer's research Increase awareness of a particular research paper |
Year(s) Of Engagement Activity | 2014 |
Description | Parkinson's UK Project visit |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Regional |
Primary Audience | Supporters |
Results and Impact | Eleven people which included one person from the Parkinson's UK Research team visited our lab in July 2013. Three lab members gave a presentation of their research followed by a visit of our lab and demonstration of the techniques used in the lab Several people suffering of PD asked to provide data about our research and findings to discuss with friends and members of their family. |
Year(s) Of Engagement Activity | 2013 |