Grants and Contributions:

Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023)

Normal brain function relies on the transfer of excitatory or inhibitory substances called neurotransmitters between neurons at specialized adhesion structures called synapses. Excitatory synapses are structurally asymmetric with neurotransmitter released from one side (the presynaptic side) and received at the other (the postsynaptic side), enabling uni-directional information communication. The development of such asymmetric synapses requires adhesion between the two sides of the synapse followed by differential but coordinated accumulation of proteins on either side. Many proteins are needed to drive this pre- and post-synaptic specialization. In particular, several proteins that can modify other proteins through a process called phosphorylation are present on one side or the other of the developing synapse. In order to coordinate synapse assembly, the actions of the pre- and post-synaptic proteins involved in phosphorylation must be linked across the synaptic cleft. Here we propose to develop a new research program to uncover molecular mechanisms underlying structural and functional asymmetry of excitatory synapses by investigating trans-synaptically-coupled phosphorylation pathways.

Based on our preliminary data, we will focus on the actions of one particular protein pair: TrkC-PTPσ. TrkC is present post-synaptically and is a kinase that can phosphorylate other proteins. TrkC binds to PTPσ which is present pre-synaptically and can de-phosphorylate substrates. This protein interaction promotes formation of excitatory synapses but it is not known through which phosphorylation signalling pathways this occurs. Using genetically modified mice in which TrkC and PTPσ interaction is abolished and advanced techniques in molecular and cellular biology and biochemistry, we will identify the signalling pathways invoked by the TrkC-PTPσ complex at synapses and then examine how manipulation of these pathways alters synapse formation and function. We will also use the genetically modified mice to investigate how TrkC-PTPσ interaction is involved in synapse development in a whole-organism setting.

This program will test a novel concept in synapse development: how coordinated trans-synaptic phosphorylation drives synapse asymmetry. Also, because some of the proteins that we will study are also involved in other tissues, the characterization of the genetically modified mice may address more general questions about how biological asymmetry is determined. Therefore, this program will have a strong impact in multiple biological science fields. Furthermore, since the proposed study will employ state-of-the-art experimental approaches in molecular and cellular biology, biochemistry, genetic engineering and electrophysiology, this program will also provide an innovative multidisciplinary training environment for graduate and undergraduate students in Canada.