Ann Marie Craig, Ph.D.
Professor of Psychiatry
Canada Research Chair in Neurobiology
Brain Research Centre
Koerner Pavillion Room F149
University of British Columbia
2211 Wesbrook Mall
Canada V6T 2B5
- BSc Biochemistry, Carleton University
- PhD Biochemistry, University of Western Ontario
- PDF Neuroscience, National Institutes of Health, USA
- PDF Neuroscience, University of Virginia, USA
- Excitatory and inhibitory synapses
- Synapse development and plasticity
- Synapse organizing proteins
- Neurotransmitter receptors
- Autism and schizophrenia
Specialized connections between nerve cells, called synapses, are the basic units of communication in the brain. We are interested in how nerve cells in the brain make synaptic connections and modify connections with experience. We study these questions of synapse development and synapse plasticity mainly from a cellular and molecular viewpoint.
What are the molecular triggers that initiate central neuron synapse formation? How do neurotransmitter-filled vesicles and associated release and recycling machinery in axons and neurotransmitter receptors and associated signaling molecules in dendrites become precisely aligned at appropriate nerve cell contacts? How do excitatory glutamate and inhibitory GABA receptors traffic to appropriate synapses, and how are such processes regulated by activity? We use neuron culture, molecular biology, live cell fluorescence imaging, mouse molecular genetics and electrophysiology to answer these questions.
This fundamental research bears directly on psychiatric disorders. Genetic variants in multiple synaptic organizing complexes are linked to autism spectrum disorders and schizophrenia. It is our belief that the cellular molecular level studies and animal models we are developing will contribute to rational and effective therapies for these disorders
(Click on image to enlarge)
Bird on a Wire:
An unbiased expression screen for proteins able to induce presynaptic differentiation in contacting axons identified the leucine-rich repeat transmembrane protein LRRTM1. The image shows LRRTM1-CFP (blue) expressed on a non-neuronalcell inducing clustering of synapsin (red) in contacting axons. These induced presynaptic specializations are similar to specializations marked by synapsin clusters at sites of axon contact with dendrites (green, MAP2).
Synapse Organizing Proteins
We developed a unique unbiased expression screen for proteins that induce presynaptic differentiation in contacting axons. Through this screen, we re-isolated postsynaptic neuroligins and identified additional synaptogenic proteins including LRRTMs, the neurotrophin receptor TrkC, and the Slitrk family. Remarkably, all of these postsynaptically localized synaptogenic proteins act via binding two families of presynaptically localized partners, neurexins and type IIA protein tyrosine phosphatases (PTPs). Specific isoforms of neurexins and PTPs generated from different genes and by alternative splicing associate with different postsynaptic partners to regulate synapse development. We are working towards understanding the full significance of the binding code among these synaptic organizing proteinsand studying novel candidates.
Many synaptic organizing proteins including neurexins, PTPs, neuroligins, and LRRTMs are linked to neurodevelopmental disorders, most commonly to autism. Collaboratively, we identified novel function-altering variants inneurexingenes in autism and schizophrenia. Using mouse molecular genetics, a major ongoing emphasis is to understand the role of synapse organizing proteins in controlling synaptic structure, composition, and function in specific pathways in vivo. Our hope is to develop targeted reagents that may correct imbalances due to loss of specific genes.
Inhibitory GABAergic Synapses
Less is known about the molecular composition of inhibitory GABAergic synapses in comparison with excitatory glutamatergic synapses. In addition to studying organizing proteins selective for inhibitory synapses including neuroligin-2 and Slitrk3, we are using a combined genetic and proteomics approach to identify novel GABA receptor interacting proteins and other components of inhibitory synapses. We are also using live cell imaging to study long term dynamics of inhibitory synapses and specification mechanisms for inhibitory versus excitatory synapses.
Excitatory Glutamatergic Synapses
Over the years, we contributed to identifying several molecular components of glutamatergic postsynaptic sites. Recent studies focus on mechanisms of synaptic targeting of NMDA type glutamate receptors and of a key enzyme calcium/calmodulin-activated kinase CaMKII as well as excitatory-specific synaptic organizing complexes. These studies contribute towards understanding mechanisms of synaptic plasticity associated with and homeostatic regulation and learning and memory.
Ina Ammendrup-Johnsen, Postdoctoral Fellow
Sarah Au-Yeung, Undergraduate Research Assistant
Claire Bomkamp, Graduate Student
Steven Connor, Postdoctoral Fellow
Frederick Dobie, Postdoctoral Fellow
Nazarine Fernandes, Research Technician
Yuan Ge, Postdoctoral Fellow
Lin Luo, Graduate Student
Kevin She, MSc, Graduate Student
Tabrez Siddiqui, Postdoctoral Fellow
Hideto Takahashi, Postdoctoral Fellow
Parisa Karimi Tari, Graduate Student
Peng Zhang, Postdoctoral Fellow
Xiling Zhou, Research Technician
She K, Rose JK, Craig AM. 2012. Differential stimulus-dependent synaptic recruitment of CaMKIIα by intracellular determinants of GluN2B. Mol. Cell. Neurosci. 51:68–78.
She K, Ferreira J, Carvalho AL, Craig AM. 2012. Glutamate binding to GluN2B controls surface trafficking of N-Methyl-D-aspartate (NMDA) receptors. J. Biol. Chem. 287:27432-45;
[highlighted as J. Biol. Chem. Paper of the Week with cover photo].
Takahashi H, Katayama K, Sohya K, Miyamoto H, Prasad T, Matsumoto Y, Ota M, Yasuda H, Tsumoto T, Aruga J# Craig AM# (# co-corresponding authors). 2012. Selective control of inhibitory synapse development by Slitrk3-PTPδ trans-synaptic interaction. Nat.Neurosci. 15:389-398.
Kaufman A, Milnerwood A, Sepers M, Coquinco A, She K, Wang L, Lee H, Craig AM, Cynader M, Raymond L. 2012. Opposing roles of synaptic and extrasynaptic NMDA receptor signaling in co-cultured striatal and cortical neurons. J. Neurosci. 32:3992-400.
Takahashi H, Arstikaitis P, Prasad T, Bartlett T, Wang YT, Murphy TH, Craig, AM. 2011. Postsynaptic TrkC and presynaptic PTPσ function as a bidirectional excitatory synaptic organizing complex. Neuron 69:287-303.
[highlighted by Faculty of 1000 multiple citations].
Gauthier J*, Siddiqui TJ*, Huashan P, Yokomaku D, Hamdan FF, Champagne N, Spiegelman D, Noreau A, Lafrenière RG, Fathalli F, Joober R, Krebs MO, DeLisi LE, Mottron L, Fombonne E, Michaud JL, Drapeau P, Carbonetto S, Craig AM#, Rouleau GA# (*co-first authors; # co-corresponding authors). 2011. Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Human Genet.130:563-73.
Dobie F, Craig AM. 2011. Inhibitory synapse dynamics: Coordinated presynaptic and postsynaptic mobility and the major contribution of recycled vesicles to new synapse formation. J. Neurosci. 31:10481-93.
[highlighted by Faculty of 1000].
Ferreira J, Rooyakkers A, She K, Ribeiro L, Carvalho AL#, Craig AM# (# co-corresponding authors). 2011. Activity and protein kinase C regulate synaptic accumulation of NMDA receptors independently of GluN1 splice variant. J. Biol. Chem. 286:28331-28342.
She K, Craig AM. 2011. NMDA receptors mediate synaptic competition in culture. PLoS One 6:e24423.
Siddiqui TJ, Craig AM. 2011. Synaptic organizing complexes. Curr. Opin. Neurobiol.21:132-143.
Soto F, Bleckert A, Lewis R, Kang Y, Kerschensteiner D, Craig AM, Wong ROL. 2011. Coordinated increase in inhibitory and excitatory synapses onto retinal ganglion cells during development. Neural Dev. 6:31.
Siddiqui TJ, Pancaroglu R, Kang Y, Rooyakkers A, Craig AM. 2010. LRRTMs and neuroligins bind neurexins with a differential code to cooperate in glutamate synapse development. J. Neurosci.30:7295-7506.
[highlighted by Simons Foundation for Autism Research].
Linhoff, MW, Lauren, J, Cassidy RM, Dobie FA, Takahashi H, Nygaard HB, Airaksinen MS, Strittmatter SM, Craig, AM. 2009. An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. Neuron 61:734-749.
[highlighted by Brose, N. (2009) Synaptogenic proteins and synaptic organizers: "Many hands make light work". Neuron 61:650-652. and by Faculty of 1000].
Rose, J., Jin, S.X., Craig AM. 2009. Heterosynaptic molecular dynamics: Locally-induced propagating synaptic accumulation of CaM kinase II. Neuron 61:351-358.
[highlighted by Klassen, MP and Shen, K (2009) The curious case of a wandering kinase: CaMKII spreads the wealth. Neuron 61:331-332. and by Faculty of 1000].
Kang Y, Zhang X, Dobie F, Wu H, Craig AM. 2008. Induction of GABAergic postsynaptic differentiation by α-neurexins. J. Biol. Chem. 283:2323-34.
Laezza F, Gerber BR, Lou JY, Kozel M, Hartman H, Craig AM, Ornitz DM, Nerbonne JM. 2007. The FGF14F145S mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability. J. Neurosci. 27:12033-44.
Dobie F, Craig AM. 2007. A fight for neurotransmission: SCRAPPER trashes RIM. Cell 130:775-7.
Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, Wu DC, Lu J, Tymianski M, Craig AM, Wang YT. 2007. NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J. Neurosci. 27:2846-57.
Craig AM, Kang Y. 2007: Neurexin-neuroligin signaling in synapse development. Curr. Opin. Neurobiol. 17:43-52.
Laezza F, Wilding TJ, Sequeira S, Coussen F, Zhang XZ, Hill-Robinson R, Mulle C, Huettner JE, Craig AM. 2007. KRIP6: A novel BTB/kelch protein regulating function of kainate receptors. Mol. Cell. Neurosci. 34:539-50.
Schlief ML, West T, Craig AM, Holtzman DM, Gitlin JD. 2006: Role of the Menkes copper transporting ATPase in NMDA receptor-mediated neuronal toxicity. Proc. Natl. Acad. Sci. USA 103:14919-24.
Kang Y, Craig AM. 2006: Composition and assembly of GABAergic postsynaptic specializations. In: Molecular Mechanisms of Synaptogenesis (A Dityatev and A El-Husseini, eds.) Springer, New York, pp. 277-95.
Graf ER, Kang Y, Hauner A, Craig AM. 2006: Structure-Function and Splice Site Analysis of the Synaptogenic Activity of the Neurexin-1β LNS Domain. J. Neurosci. 26:4256-65.
Sharma K, Fong DK, Craig AM. 2006. Postsynaptic protein mobility in dendritic spines: Long-term regulation by synaptic NMDA receptor activation. Mol. Cell. Neurosci. 31:702-12.
Craig AM, Graf ER, Linhoff MW. 2006. How to build a central synapse: Clues from cell culture. Trends Neurosci. 29:8-20.
Lou J, Laezza F, Gerber BR, Xiao M, Yamada KA, Hartmann H, Craig AM, Nerbonne JM, Ornitz DM. 2005. Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels. J. Physiol. 569:179-93.
Harms KJ, Tovar KR, Craig AM. 2005. Synapse-specific regulation of AMPA receptor subunit composition by activity. J. Neurosci. 25:6379-88.
Harms KJ, Craig AM. 2005. Synapse composition and organization following chronic activity blockade in cultured hippocampal neurons. J. Comp. Neurol. 490:72-84.
Waites CL, Craig AM, Garner CC. 2005. Mechanisms of vertebrate synaptogenesis. Annu. Rev. Neurosci. 28:251-74.
Graf E, Zhang X, Jin SX, Linhoff M, Craig AM. 2004. Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119:1013-26.
Schlief ML, Craig AM, Gitlin JD. 2004. NMDA receptor activation mediates copper homeostasis in hippocampal neurons. J Neurosci. 25:239-246.
Levi S, Logan SM, Tovar KR, Craig AM. 2004. Gephyrin is critical for glycine receptor clustering but not for the formation of functional GABAergic synapses in hippocampal neurons. J. Neurosci. 24:207-17.
Wang X, Weiner JA, Levi S, Craig AM, Bradley A, Sanes JR. 2002. Gamma protocadherins are required for survival of spinal interneurons. Neuron 36:843-54.
Levi S, Grady RM, Henry MD, Campbell KP, Sanes JR, Craig AM. 2002. Dystroglycan is selectively associated with inhibitory GABAergic synapses but is dispensable for their differentiation. J. Neurosci. 22:4274-85.
Fong DK, Rao A, Crump FT, Craig AM 2002. Rapid synaptic remodeling by protein kinase C: reciprocal translocation of NMDA receptors and calcium/calmodulin-dependent kinase II. J. Neurosci. 22:2153-64.
Boudin H, Craig AM. 2001. Molecular determinants for PICK1 synaptic aggregation and mGluR7 receptor coclustering: role of the PDZ, coiled-coil, and acidic domains. J. Biol. Chem. 276: 30270-76.
Crump FT, Dillman KS, Craig AM. 2001. cAMP-dependent protein kinase mediates activity-regulated synaptic targeting of NMDA receptors. J. Neurosci. 21:5079-88.
Craig AM, Boudin H. 2001. Molecular heterogeneity of central synapses: afferent and target regulation. Nat. Neurosci. 4:569-78.
Boudin H, Doan A, Xia J, Shigemoto R, Huganir RL, Worley P, Craig AM. 2000. Presynaptic clustering of mGluR7 requires the PICK1 PDZ domain binding site. Neuron 28:485-97.
Rao A, Cha EM, Craig AM. 2000. Mismatched appositions of presynaptic and postsynaptic elements in isolated hippocampal neurons. J. Neurosci. 20:8344-53.
Allison DW, Chervin AS, Gelfand VI, Craig AM. 2000. Postsynpatic scaffolds of excitatory and inhibitory synapses in hippocampal neurons: maintenance of core components independent of actin filaments and microtubules. J. Neurosci. 20:4545-54.
Stowell JN, Craig AM. 1999. Axon / dendrite targeting of metabotropic glutamate receptors by their cytoplasmic carboxy terminal domains. Neuron 22:525-36.
Serpinskaya AS, Feng G, Sanes JR, Craig AM. 1999. Synapse formation by hippocampal neurons from agrin-deficient mice. Dev. Biol. 205:65-78.
Craig AM. 1998. Activity and synaptic receptor targeting: the long view. Neuron 21:459-62.
Allison DW, Spector I, Gelfand VI, Craig AM. 1998. Role of actin in anchoring postsynaptic receptors in cultured hippocampal neurons: Differential attachment of NMDA versus AMPA receptors. J. Neurosci. 18:2423-36.
Rao A, Kim E, Sheng M, Craig AM. 1998. Heterogeneity in the molecular composition of excitatory postsynaptic sites during development of hippocampal neurons in culture. J. Neurosci. 18:1217-29.
Wyszynski M, Lin J, Rao A, Nigh E, Beggs AH, Craig AM, Sheng M. 1997. Competitive binding of α-actinin and calmodulin to the NMDA receptor. Nature 385:439-42.
Rao A, Craig AM. 1997. Activity regulates the synaptic localization of the NMDA receptor in hippocampal neurons. Neuron 19:801-812.
Craig AM, Wyborski RJ, Banker G. 1995. Preferential addition of newly synthesized membrane protein at axonal growth cones. Nature 375:592-594.
Craig AM, Banker G. 1994. Neuronal polarity. Annu. Rev. Neurosci. 17:267-310.
Craig AM, Blackstone CD, Huganir RL, Banker G. 1994. Selective clustering of glutamate and &gammma;-aminobutyric acid receptors opposite terminals releasing the corresponding neurotransmitters. Proc. Natl. Acad. Sci. USA 91:12373-12377.
Craig AM, Blackstone CL, Huganir RL, Banker G. 1993. The distribution of glutamate receptors in cultured rat hippocampal neurons: Postsynaptic clustering of AMPA-selective subunits. Neuron 10:1055-1068.