Professor, Department of Psychiatry, Faculty of Medicine, UBC
Canada Research Chair in Neurobiology
DMCBH Koerner Labs, Koerner Pavillion Room F149 University of British Columbia 2211 Wesbrook Mall Vancouver BC Canada V6T 2B5
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 in neuron cultures to electrophysiological recording and serial block face scanning electron microscopy of neural circuits in genetically targeted mouse models to expansion microscopy of human clinical samples. Further, we are working to develop targeted reagents to correct synaptic imbalances in autism, schizophrenia, epilepsy, 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 implicated in autism and schizophrenia. 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. Another current project uses a novel expansion microscopy approach on clinical specimens towards understanding synaptic diversity and its role in epilepsy.
Long (Edward) Zuo, Graduate Student
Yuan Ge, Research Associate
Hong Lu, Graduate Student
Shinichiro Oku, Research Associate
Peng Zhang, Research Associate
Xiling Zhou, Lab Manager
Mathias Delhaye, Visiting Graduate Student
Connor SA*, Ammendrup-Johnsen I*, Chan AW*, Kishimoto YV*, Murayama C, Kurihara N, Tada A, Ge Y, Lu H, Yan R, LeDue JM, Matsumoto H, Kiyonari H, Kirino Y, Matsuzaki F, Suzuki T, Murphy TH, Wang YT#, Yamamoto T#, Craig AM#. *Co-first author, #co-corresponding author. 2016. Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2. Neuron 91:1052-68. doi: 10.1016/j.neuron.2016.08.016.
[highlighted by Canadian Association for Neuroscience website]
Elegheert J, Cvetkovska V, Clayton AJ, Heroven C, Vennekens KM, Smukowski SN, Regan MC, Jia W, Smith AC, Furukawa H, Savas JN, de Wit J, Begbie J, Craig AM#, Aricescu AR#. #Co-corresponding author. 2017. Structural Mechanism for Modulation of Synaptic Neuroligin-Neurexin Signaling by MDGA Proteins. Neuron 95:896-913. doi: 10.1016/j.neuron.2017.07.040.
[highlighted by Neuron 2017 95:729-732.]
Connor SA, Ammendrup-Johnsen I, Kishimoto Y, Karimi Tari P, Cvetkovska V, Harada T, Ojima D, Yamamoto T, Wang YT, Craig AM. 2017. Loss of Synapse Repressor MDGA1 Enhances Perisomatic Inhibition, Confers Resistance to Network Excitation, and Impairs Cognitive Function. Cell Rep. 2017 21:3637-3645. doi: 10.1016/j.celrep.2017.11.109.
Ge Y, Kang Y, Cassidy RM, Moon KM, Lewis R, Wong ROL, Foster LJ, Craig AM. 2018. Clptm1 Limits Forward Trafficking of GABAA Receptors to Scale Inhibitory Synaptic Strength. Neuron 93: 596-610. doi: 10.1016/j.neuron.2017.12.038.
[highlighted by Neuron 2018 97: 479-481.]
Bhouri M, Morishita W, Temkin P, Goswami D, Kawabe H, Brose N, Südhof TC, Craig AM, Siddiqui TJ#, Malenka R#. 2018. Deletion of LRRTM1 and LRRTM2 in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons. PNAS doi: 10.1073/pnas.1803280115.
Zhang P, Lu H*, Peixoto RT*, Pines MK*, Ge Y, Oku S, Siddiqui TJ, Xie Y, Wu W, Archer-Hartmann S, Yoshida K, Tanaka KF, Aricescu AR, Azadi P, Gordon MD, Sabatini BL, Wong ROL, Craig AM. *Co-second author. 2018. Heparan sulfate organizes neuronal synapses through neurexin partnerships. Cell 174:1450-1464.
[highlighted by Cell 2018 174:1337-1338 and by DMCBH and UBC Faculty of Medicine.]
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