Craig, Ann Marie

Specialized connections between nerve cells, called synapses, are the basic units of communication in the brain. We study how brain cells make synaptic connections and how these connections are altered in neuropsychiatric disorders. We use a range of approaches from molecular manipulations and live cell fluorescence imaging in neuron cultures to electrophysiological recording and serial block face scanning electron microscopy of neural circuits in mouse models.

From a unique unbiased expression screen, we identified multiple novel synaptic organizers for excitatory and inhibitory synapses. In a combinatorial manner, these synaptic organizers control the development and functional properties of synapses in all brain circuits. Genetic variants in these synaptic organizing complexes increase risk for autism spectrum disorders and schizophrenia, and new evidence suggests that their interactions contribute to Alzheimer's disease. Using mouse molecular genetics, a major ongoing emphasis is to understand the role of synapse organizing proteins and their post-transcriptional modulation in controlling synaptic structure, composition, and function in specific pathways in vivo. Further, we are working to develop targeted reagents to correct synaptic imbalances in autism, schizophrenia, and Alzheimer's disease.

To highlight a few examples of our recent research, among the synaptic organizers we identified, LRRTMs are now studied as central to the process of long term potentiation which is thought to be a cellular basis for learning and memory. Our discovery of suppressors of synaptic organizing proteins led to the characterization of MDGA2 haploinsufficient mice with altered excitation/inhibition balance as a new model for autism (https://can-acn.org/ubc-researchers-may-have-found-how-electrical-volume...).  In another combined genetic and proteomics screen to identify novel GABA receptor interacting proteins, we identified an unusual regulator that scales inhibitory synaptic strength, which could be harnessed to correct imbalances in excitation/inhibition. Recently, we discovered an essential role for a rare glycan modification in the canonical neurexin-neuroligin synaptic organizing complex. Remarkably, mice lacking this single sugar modification on neurexin-1 have severe structural and functional deficits in hippocampal synapses and reduced survival. These findings reveal a new set of neurexin interacting proteins, another level of regulation through glycan fine structure, and a novel direction for therapeutic intervention. A current research focus is to understand the role of such post-transcriptional modifications of synaptic organizing complexes in brain development and to harness this knowledge to develop therapeutics for neuropsychiatric disorders. These research directions are also spreading internationally as several of these findings have lead to independent research programs for former trainees.