2350 Health Sciences Mall, Rm 2420 Life Sciences Institute, University of British Columbia Vancouver BC V6T 1Z3 Canada

Research Goals

  • To understand the molecular mechanisms by which synaptic connections in the brain are formed, remodeled and eliminated;
  • To determine how disruptions in the formation and/or plasticity of synaptic connections perturb brain function;
  • To determine whether restoring synaptic function in the diseased brain can normalize cognitive and functional abilities.

Synapses of the central nervous system are highly specialized regions of cell-cell contact designed to rapidly and efficiently relay signals from one neuron to another. By establishing a dynamic yet precise network of synaptic connections, the brain is able to attain a level of functional complexity that enables not only simple motor tasks, but also sophisticated emotional and cognitive behaviour. The study of how synapses form and function is therefore essential to our ultimate understanding of higher brain functions such as learning and memory as well as our understanding of how things go awry in neurodevelopmental and neurodegenerative disorders such as intellectual disabilities, schizophrenia, autism, anxiety disorders, addiction and Alzheimer’s disease.

How do palmitoylating enzymes regulate synaptic connectivity and learning?

Our work demonstrates that DHHC enzymes, which mediate the posttranslational palmitoylation of proteins, are master regulatory ‘hubs’ for activity-dependent structural and functional plasticity critical to proper circuit formation (Nat Neurosci, 2014; Nat Commun, 2015). Building on these findings, we are currently exploring the roles of these enzymes in regulating synapse formation and plasticity, cognition and behavior. This is exceedingly important as 9 of the 23 DHHC enzymes have been linked to neurological disorders thus far and ~41% of all synaptic proteins are substrates for palmitoylation. We are one of a few labs worldwide studying this fundamental process in the brain.

How do adhesion complexes regulate synaptic connectivity and learning?

Our lab has demonstrated a role for cadherin adhesion complexes in synapse formation and plasticity, as well as cognition and behavior. Most recently, we demonstrated that increased cadherin-based adhesion at synapses of the reward circuit can block drug-seeking behaviors associated with addiction (Nat Neurosci, 2017). This study was an extension of our previous work elucidating molecular mechanisms underlying synapse formation (Neuron, 2003; J Biol Chem, 2008; Mol Cell Biol, 2009; J Biol Chem, 2010; Neurosci, 2010; J Neurosci, 2011), as well as our work demonstrating that cadherins promote synapse formation and plasticity in vivo (Neuron, 2003; PNAS, 2014).