Min Zhuo

Research Synopsis

Research Interests: Genetic models for neurological and psychiatric diseases; Synaptic transmission and regulation Synaptic plasticity: long-term potentiation and depression; Physiological and athological related central plastic changes: synaptic responses and action potentials; Memory, emotion, sensation, stress and cortical reorganization; Alzheimer’s disease, aging and persistent pain.

Detailed Description:

We are interested in the cellular mechanisms of synaptic transmission and plasticity in the central nervous system and functional implications of such plastic changes. Long-term plastic changes in synaptic transmission are believed to contribute to information storage in the brain. The laboratory employs a combination of genetic, electrophysiological, pharmacological and behavioral approaches. At the single neuron level, whole-cell patch clamp recordings of synaptic responses are made from single neurons in brain and spinal cord slices. At the system level, neuronal evoked responses in intact or freely moving animals are performed to study neuronal plasticity in emotional learning, persistent pain and drug addiction. At the behavioral level, a combination of pharmacological and genetic approaches in mice (genetic mutant mice) allows us to study molecular mechanisms of emotional fear memory and pain.

The current research projects are: (1) molecular and synaptic mechanisms for emotional fear memory; (2) glutamatergic synaptic transmission and regulation at sensory synapses; (3) genetic manipulation of NMDA NR2B receptors in the anterior cingulate cortex and its functional implications such as pain and pleasure; (4) aging related changes in central plasticity and behavioral learning. We believe that these studies performed at different levels, from neuron to behavior, will help us to understand the mechanisms of central synaptic plasticity, in particular those underlying fear memory and persistent pain.

METHODS USED

Procedures: Behavioural tests, in-vitro electrophysiology, in-vivo electrophysiology.

EQUIPMENT USED

Amplifier (Molecular Device Multiclamp 7000A; Molecular Device Axopatch 200B), analytical balances (Mettler Toledo, AB54-S), benchtop centrifuge, confocal microscope (Olympus, Fluoview 1000), Cryostat (Leica, CM3050S), Digidata (Molecular device, 1322 A), fluorescence microscope (Olympus, BX51), fresh tissue sectioning systems (Wanner instrument, vibratome 1000), low and ultralow freezers, micropipette puller (Sutter Instrument Company, P-97), motorized micromanipulators (Sutter Instrument Company, MP-285), pneumatic picopump (PV820, WPI), pressure osmometer (Vapro 5520), ProBlot hybridization oven, setups for electropherosis, stimulator (Grass, S88), stirrer/hot plate, water baths.

PRESENT TRAINEES

Xiangyao Li
Tao Chen
Kohei Koga
Shuang Qiu
Anett Shumacher
Giannina Descalzi
Su-eon Sims
Heather Kang
Flora Nasri
Kaori Yamada 

Opening positions for graduate and postdoc fellows

PRESENT COLLABORATIONS

Outside the Department of Physiology:
Kaang Bong-Kiun, Seoul National University
Kida Satoshi, Tokyo Agriculture University
HK Manji, NIH, USA
T Abel, USA, UP
BM Li, China
Jose Naranjno, Spain
Graham Collingridge, UK
YQ Li, China

Committee member/Officer of national or international scientific organization:
Alzheimer's Association (2011)
Agence National DE LA Recherche ANR (2011)
National Science Foundation, China (2011)
American Institute of Biological Sciences (2011)
Agence National DE LA Recherche ANR (2012)
National Science Foundation, China (2012)
Alzheimer's Association (2012)
Agence National DE LA Recherche ANR (2011)
National Science Foundation, China (2011)
American Institute of Biological Sciences (2011)
Agence National DE LA Recherche ANR (2012)
National Science Foundation, China (2012)
Alzheimer's Association (2012)
Agence National DE LA Recherche ANR, France (2013)
Chang Jian Scholar review, China (2013)
UK Wellcome Trust Senior investigator review (2013)
UK MRC research grant review (2013)
China, National Science Foundation major grant for Neurosciences (2013)
Connaught Program new investigator award (2013)
Israel Science Foundation (2013)
Netherlands Organizationon for Scientific Research (2013)
Vienna Science and Technology Fund (WWTF) (2013)
Human Frontier Science Porgram (2013)
NSEC, Discovery grant, Canada (2013)

Recent Publications

Li, P., and Zhuo, M . (1998). Silent glutamatergic synapses and nociception in mammalian spinal cord. Nature 393, 695-698.

Li, P., Kerchner, G. A., Sala, C., Wei, F., Huettner, J. E., Sheng, M., and Zhuo, M . (1999). AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses. Nat Neurosci 2, 972-977.

Li, P., Wilding, T. J., Kim, S. J., Calejesan, A. A., Huettner, J. E., and Zhuo, M . (1999). Kainate-receptor-mediated sensory synaptic transmission in mammalian spinal cord. Nature 397, 161-164.

Tang, Y. P., Shimizu, E., Dube, G. R., Rampon, C., Kerchner, G. A., Zhuo, M. , Liu, G., and Tsien, J. Z. (1999). Genetic enhancement of learning and memory in mice. Nature 401, 63-69.

Kerchner, G. A., Wang, G. D., Qiu, C. S., Huettner, J. E., and Zhuo, M. (2001). Direct presynaptic regulation of GABA/glycine release by kainate receptors in the dorsal horn: an ionotropic mechanism. Neuron 32, 477-488.

Wei, F., Wang, G. D., Kerchner, G. A., Kim, S. J., Xu, H. M., Chen, Z. F., and Zhuo, M . (2001). Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat Neurosci 4, 164-169.

Wei, F., Qiu, C. S., Kim, S. J., Muglia, L., Maas, J. W., Pineda, V. V., Xu, H. M., Chen, Z. F., Storm, D. R., Muglia, L. J., and Zhuo, M. (2002). Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron 36, 713-726.

Wei, F., Qiu, C. S., Liauw, J., Robinson, D. A., Ho, N., Chatila, T., and Zhuo, M . (2002). Calcium calmodulin-dependent protein kinase IV is required for fear memory. Nat Neurosci 5, 573-579.

Zhao, MG, Toyoda, H, Lee, YS, Wu ,LJ, Ko, SW, Zhang, XH, Jia, Y, Shum, F, Xu, H, Li, BM, Kaang, BK and Zhuo, M. (2005). Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory. Neuron 47, 859-872.

Wang H, Wu LJ, Kim SS, Lee FJ, Gong B, Toyoda H, Ren M, Shang YZ, Xu H, Liu F, Zhao MG, Zhuo M . (2008) FMRP acts as a key messenger for dopamine modulation in the forebrain. Neuron , 59:634-647.

Vecsey CG, Baillie GS, Jaganath D, Havekes R, Daniels A, Wimmer M, Huang T, Brown KM, Li XY, Descalzi G, Kim SS, Chen T, Shang YZ, Zhuo M , Houslay MD, Abel T. (2009) Sleep deprivation impairs cAMP signalling in the hippocampus. Nature 461:1122-1125.

Slutsky I, Abumaria N, Wu LJ, Huang C, Zhang L, Li B, Zhao X, Govindarajan A, Zhao MG, Zhuo M , Tonegawa S, Liu G (2010) Increasing synaptic density and enhanced memory by brain magnesium. Neuron 65:165-177.

Li XY, Ko HG, Chen T, Descalzi G, Koga K, Wang H, Kim SS, Shang Y, Kwak C, Park SW, Shim J, Lee K, Collingridge GL, Kaang BK, Zhuo M. (2010)  Alleviating neuropathic pain hypersensitivity by inhibiting PKMzeta in the anterior cingulate cortex. Science 330:1400-1404.

Wang H, Xu H, Wu LJ, Kim SS, Chen T, Koga K, Descalzi G, Gong B, Vadakkan KI, Zhang X, Kaang BK, Zhuo M. (2011) Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain. Science Translational Medicine 3(65):65ra3 (Comment in: Nat Rev Drug Discov. 2011 Mar;10(3):176).

Kim JI, Lee HR, Sim SE, Baek J, Yu NK, Choi JH, Ko HG, Lee YS, Park SW, Kwak C, Ahn SJ, Choi SY, Kim H, Kim KH, Backx PH, Bradley CA, Kim E, Jang DJ, Lee K, Kim SJ, Zhuo M, Collingridge GL, Kaang BK. (2011) PI3Kγ is required for NMDAR-dependent long-term depression and behavioral flexibility. Nat Neurosci. 2011 Oct 23;14(11):1447-54.

Nicolas CS, Peineau S, Amici M, Csaba Z, Fafouri A, Javalet C, Collett VJ, Hildebrandt L, Seaton G, Choi SL, Sim SE, Bradley C, Lee K, Zhuo M, Kaang BK, Gressens P, Dournaud P, Fitzjohn SM, Bortolotto ZA, Cho K, Collingridge GL. (2012) Jak/STAT pathway is involved in synaptic plasticity. Neuron 73:374-390. (see preview in Neuron, JAK/STAT: The Enigma within the Mystery of NMDAR-LTD p211).

Kang SJ, Liu MG, Chen T, Ko HG, Baek GC, Lee HR, Lee K, Collingridge GL, Kaang BK, Zhuo M. (2012) Plasticity of Metabotropic Glutamate Receptor-Dependent Long-Term Depression in the Anterior Cingulate Cortex after Amputation.  J Neurosci. 32:11318-11329.
Steenland HW, Li XY, Zhuo M. (2012) Predicting Aversive Events and Terminating Fear in the Mouse Anterior Cingulate Cortex during Trace Fear Conditioning. J Neurosci. 32:1082-1095.
Descalzi G, Li XY, Chen T, Mercaldo V, Koga K, Zhuo M.Mol Brain 5:6.
Koga K, Sim SE, Chen T, Wu LJ, Kaang BK, Zhuo M. (2012) Kainate receptor-mediated synaptic transmissions in the adult rodent insular cortex.  J Neurophysiol. 108:1988-1998.
Li XY, Chen T, Descalzi G, Koga K, Qiu S, Zhuo M. (2012)  Characterization of neuronal intrinsic properties and synaptic transmission in layer I of anterior cingulate cortex from adult mice.  Mol Pain. 8:53. 
Wang H, Morishita Y, Miura D, Naranjo JR, Kida S, Zhuo M. (2012)  Roles of CREB in the regulation of FMRP by group i metabotropic glutamate receptors in cingulate cortex.  Mol Brain. 5:27.
Descalzi G, Fukushima H, Suzuki A, Kida S, Zhuo M. (2012) Genetic enhancement of neuropathic and inflammatory pain by forebrain upregulation of CREB-mediated transcription. Mol Pain. 8:90.
Qiu S, Chen T, Koga K, Guo YY, Xu H, Song Q, Wang JJ, Descalzi G, Kaang BK, Luo JH, Zhuo M, Zhao MG. (2013) An Increase in Synaptic NMDA Receptors in the Insular Cortex Contributes to Neuropathic Pain.  Sci Signal. 6:ra34 (Cover page story). 
Liu MG, Kang SJ, Shi TY, Koga K, Zhang MM, Collingridge GL, Kaang BK, Zhuo M. (2013) Long-term potentiation of synaptic transmission in the adult mouse insular cortex: multi-electrode array recordings. J Neurophysiol.110:505-521 (Editor’s Choice).
Liu MG, Koga K, Guo YY, Kang SJ, Collingridge GL, Kaang BK, Zhao MG, Zhuo M. (2013) Long-term depression of synaptic transmission in the adult mouse insular cortex in vitro.  Eur J Neurosci. 38:3128-45.
Descalzi G, Chen T, Koga K, Li XY, Yamada K, Zhuo M. (2013) Cortical GluK1 kainate receptors modulate scratching in adult mice. J Neurochem. 126:636-50.
Kang SJ, Liu MG, Shi TY, Zhao MG, Kaang BK, Zhuo M. (2013) N-type voltage gated calcium channels mediate excitatory synaptic transmission in the anterior cingulate cortex of adult mice.  Mol Pain. 9:58.
Mellström B, Sahún I, Ruiz-Nuño A, Murtra P, Gomez-Villafuertes R, Savignac M, Oliveros JC, Gonzalez P, Kastanauskaite A, Knafo S, Zhuo M, Higuera-Matas A, Errington ML, Maldonado R, DeFelipe J, Jefferys JG, Bliss TV, Dierssen M, Naranjo JR. (2014) DREAM controls the on/off switch of specific activity-dependent transcription pathways.  Mol Cell Biol. 34(5):877-87.
Liu MG, Zhuo M. (2014) Loss of long-term depression in the insular cortex after tail amputation in adult mice.  Mol Pain. 10:1.

Chen T, Lu JS, Song Q, Liu MG, Koga K, Descalzi G, Li YQ, Zhuo M. (2014) Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome.  Neuropsychopharmacology. 2014 Feb 20. doi: 10.1038/npp.2014.44. [Epub ahead of print].Liu MG, Zhuo M. (2014) No requirement of TRPV1 in long-term potentiation or long-term depression in the anterior cingulate cortex.  Mol Brain. 7:27.

Reviews:

Zhuo, M. (2000). Silent glutamatergic synapses and long-term facilitation in spinal dorsal horn neurons. Prog Brain Res 129, 101-113.

Zhuo, M. (2002). Glutamate receptors and persistent pain: targeting forebrain NR2B subunits. Drug Discov Today 7, 259-267.

Zhuo, M. (2004). Central plasticity in pathological pain. Novartis Found Symp 261, 132-145; discussion 145-154.

Zhuo, M. (2005). Canadian Association of Neuroscience review: Cellular and synaptic insights into physiological and pathological pain. EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health lecture. Can J Neurol Sci 32, 27-36.

Zhuo, M. (2008) Cortical plasticity and chronic pain. Trends Neuroscience, 31:199-207. (Review)

Wu LJ, Zhuo M. (2009) Targeting the NMDA Receptor Subunit NR2B for the Treatment of Neuropathic Pain. Neurotherapeutics 6:693-702.

Kim SS, Descalzi G, Zhuo M (2010) Investigation of molecular mechanism of chronic pain using genetically-engineered mice. Current Genomics, 11:70-76 (review).

Li XY, Ko HG, Chen T, Collingridge GL, Kaang BK, Zhuo M. (2011) Erasing injury-related cortical synaptic potentiation as a new treatment for chronic pain. J Mol Med (Berl)89:47-8554 7]

Zhuo M (2012) Targeting neuronal adenylyl cyclase for the treatment of chronic pain. Drug Discovery Today, Jan 26. [Epub ahead of print]

Wang H and Zhuo, M (2012) Group I metabotropic glutamate receptor-mediated gene transcription and implications for synaptic plasticity and diseases.   Front Pharmacol. 3:189.   

 Zhuo, M (2012) Cortical depression and potentiation: basic mechanisms for phantom pain, Experimental Neurobiology, Exp Neurobiol. 21:129-135.

 Zhuo, M (2013) Long-term potentiation in the anterior cingulate cortex and chronic pain.  Philos Trans R Soc Lond B Biol Sci. 369:20130146.

Park P, Volianskis A, Sanderson TM, Bortolotto ZA, Jane DE, Zhuo M, Kaang BK, Collingridge GL.(2013) NMDA receptor-dependent long-term potentiation comprises a family of temporally overlapping forms of synaptic plasticity that are induced by different patterns of stimulation. Philos Trans R Soc Lond B Biol Sci. 369:20130131.