4 YEAR PhD IN NEUROSCIENCE
Patricia C. Salinas
Departments of Cell and Developmental Biology and Neuroscience, Physiology and Pharmacology
Synaptic plasticity & degeneration: from cell signalling to circuit function
We study the function of Wnt signalling proteins in the formation, growth and stability of synapses in the central nervous system. We use a multidisciplinary approach combining state of the art cellular imaging techniques, biochemistry, electrophysiology and behavioural studies in mice to understand how changes in structural plasticity, induced by Wnts and neuronal activity, affect synaptic transmission and whole circuit function.
Recent studies from our lab have demonstrated that Wnt proteins promote the assembly of excitatory synapses in the hippocampus by triggering distinct signalling cascades on the pre- and postsynaptic sides. For example, Wnts promote the formation and growth of dendritic spines by activating CaMKII within dendritic spines. These structural changes are associated with increased synaptic strength. We are currently investigating the molecular mechanisms that control spine development focusing on short and long term effects of Wnts and on the receptors that modulate this process.
Another important project in the lab is the contribution of Wnt signalling to synaptic stability in the adult brain. We found that blockade of Wnts using a secreted Wnt antagonist, Dkk1, leads to the rapid disassembly of synapses in mature neurons without affecting cell death. We are currently investigating how dysfunction in Wnt signalling in vivo affects the integrity of synapses.
Dysfunction in Wnt signalling contributes to Amyloid-ß (Aß) synaptic toxicity. The Wnt antagonist, Dkk1, is elevated in brain biopsies of AD patients and in the brain of some animal models for AD. Interestingly, we found that Aß rapidly induces the expression of Dkk1 in the hippocampus. Importantly blockade of Dkk1 protect synapses against Aß. Our studies strongly suggest that Dkk1 contributes to the synaptic toxicity of Aß, a finding that has important implications for developing new therapeutic targets for the treatment of AD at early stages of the disease. We are currently examining the contribution of Dkk1 in synaptic degeneration and cognitive decline in AD mouse models.
1) To determine the mechanisms that regulate the trafficking and function of Wnt receptors during activity-mediated synapse formation.
2) To investigate the mechanism that control spine growth during activity mediated synapse formation and plasticity.
3) To examine the cellular and molecular mechanisms that lead to the disassembly of synapses in neurodegenerative diseases such as Alzheimer’s.
- Stamatakou E., Marzo A., Gibb A., and Salinas PC. (2013) Activity-dependent spine morphogenesis: a role for the actin capping protein Eps8. J. Neuroscience 33: 2661-2670.
- Purro S. A., Dickins E., Salinas P.C. (2012) The Wnt antagonist Dkk1 mediates the synaptic disassembly activity of Aß: a potential role for Wnt synaptic dysfunction in Alzheimer’s disease. J. Neuroscience. 32: 3492-3498.
- Ciani L., Boyle K., Dickins E., Sahores M., Anane D., Lopes D. M., Gibb A. and Salinas P. C. (2011) Wnt-7a signalling promotes dendritic spine growth and synaptic strength through CaMKII. Proc. Nat. Acad. Sciences USA 108: 10732-7.
- Budnik V, and Salinas P.C. (2011) Wnt signaling during synaptic development and plasticity. Current Op. Neurobiology. 21: 1-9
- Sahores M, Gibb A and Salinas P.C. (2010) Frizzled-5, a receptor for the synaptic organizer Wnt7a, regulates activity-mediated synaptogenesis. Development 137: 2215-2225.
- Juan P. Henriquez J.P. Webb A., Bence M., Bildsoe H., Sahores M., Hughes S.M., and Salinas P.C. (2008) Wnt signalling promotes AChR aggregation at the neuromuscular synapse in collaboration with Agrin. Proc. Nat. Acad. Sciences USA 105: 18812-18817.
- Ciani L. and Salinas P.C. (2008) From Neuronal Activity to the Actin Cytoskeleton: A Role for CaMKKs and betaPIX in Spine Morphogenesis. Neuron 57: 3-4
- Rosso S.B., Sussman D., Wynshaw-Boris A. and Salinas P.C. (2005) Wnt signalling through Dishevelled, Rac and JNK regulates dendritic development. Nature Neurosci. 8: 34-42.
- Salinas, P.C. (2003) Backchat at the synapse. Nature 425: 464-467.
- Hall A. C., Lucas F. R. and Salinas P. C. (2000) Axonal remodelling and synaptic differentiation in the cerebellum is regulated by WNT-7a signalling. Cell 100: 525-535.