Hengye Man

Assistant Professor of Biology
Ph.D., University of Toronto, 2001

Synaptic plasticity, glutamate receptor, protein trafficking

AMPA type glutamate receptors (AMPA receptors) mediate the vast majority of excitatory synaptic transmission in the brain.   Long-lasting changes in the strength of AMPA receptor-mediated synaptic transmission is believed to be the underlying mechanism for learning and memory.   Although it is becoming clear that the expression site of the long-term synaptic plasticity is at the postsynaptic domain, the exact cellular mechanisms are not fully understood.   A new hypothesis, which has attracted a great deal of attention and received increasing amount of supporting evidence, is that the efficacy of synaptic transmission can be regulated by changing receptor abundance at the postsynaptic site via receptor trafficking.   It has been demonstrated that AMPA receptors are not static on the synaptic membrane; rather, they traffic continuously between the plasma membrane and the intracellular compartments. AMPA receptors can be inserted to the plasma membrane via SNARE-mediated vesicle fusion and internalized through clathrin-mediated endocytosis.   Modulation of the receptor trafficking process by neuronal activities and signaling cascades results in changes in the synaptic receptor numbers and the strength of synaptic transmission.  

A neuron forms thousands of synapses with axonal terminals from neurons using varied types of neurotransmitters.   To ensure efficient synaptic transmission, AMPA receptors must target to the right site (post-synaptic membrane) and the right synapses (glutamatergic rather than GABAergic).   These cellular events are all related to the complex regulation of AMPA receptor trafficking.   The main focus of our lab is to understand the cellular/molecular mechanisms underlying the AMPA receptor synaptic localization and synaptic plasticity.   Specific questions include:   What molecules and signaling pathways determine AMPA receptor synaptic expression?   How does neuronal activity regulate AMPA receptor subunit combination?   How does a neuron maintain a certain level of total receptor amount?   Does AMPA receptor abundance interact with synaptic morphology? Our research is performed mainly on cultured neurons and brain slices.   We use confocal microscopy, fluorescent protein- and quantum dot-based live-imaging techniques to study receptor trafficking, electrophysiology to analyze synaptic activities, biochemical and molecular biological methods to study proteins and signaling pathways.   

Qingming Hou, Dawei Zhang, Larissa Jarzylo, Richard. L. Huganir, Heng-Ye Man. 2008. Homeostatic regulation of AMPA receptor expression at single hippocampal synapses. PNAS , 105(2):775-780.

Andken BB, Lim I, Benson G, Vincent JJ, Ferenc MT, Heinrich B, Jarzylo LA, Man HY, Deshler JO. 2007. 3'-UTR SIRF: a database for identifying clusters of whort interspersed repeats in 3' untranslated regions. BMC Bioinformatics. 30; 8:274.

Man HY, Sekine-Aizawa Y, Huganir RL. 2007. Regulation of {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking through PKA phosphorylation of the Glu receptor 1 subunit. PNAS, 104(9):3579-84.

Y Huang, H Y Man, Y Sekine-Aizawa, Y Han, K Juluri, H Luo, J Cheah, C Lowenstein, R L Huganir and S H Snyder. 2005.   S-nitrosylation of N-ethylmaleimide sensitive factor mediates surface expression of AMPA receptors.   Neuron, 46(4): 533-40

H Y Man, Q H Wang, W Y Lu, W Ju, G Amardian, S D'Souza, L D Liu, T P Wong, LE Becker, L Pai, F Liu, M P Wymann, JF MacDonald and YT Wang.   2003.   Selective activation of AMPA receptor-associated PI3-Kinase is required for LTP induction. Neuron, 37, 611-624

H Y Lee, K Takamiya, J S Han, H Y Man, C H Kim, G Rumbaugh, S Yu, L Ding, C He, R S Petralia, R J Wenthold, M Gallagher and R L Huganir.    2003.   Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell, 112, 631-643

H Y Man*, W Y Lu*, W Ju, W Trimble, Y T Wang and John F MacDonald.   2001.   Activation of synaptic NMDA receptors induces membrane insertion of new AMPA receptors and LTP in cultured hippocampal neurons. (* Equal contribution)    Neuron, 29, 243-254

R Q Hu, M A Cortez, H Y Man, J Roder, Y T Wang and O C Snead III.   2001.   Alteration of GluR2 expression in the rat brain following absence seizures induced by g-hydroxybutyric acid.   Epilepsy Research, 44(1), 41-51

R Q Hu, M A Cortez, H Y Man, J Roder, Z P Jia, Y T Wang and O C Snead III.   2001.   GHB-induced absence seizures in GluR2 null mutant mice.    Brain Research, 897 (1-2): 27-35

H Y Man, J Lin, W Ju, G Ahmadian, L Liu, L E Becker, M Sheng and Y T Wang.   2000.   Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron, 25:649-662

H Y Man, W Ju, G Ahmadian and Y T Wang.   2000.   Intracellular trafficking of AMPA receptors in synaptic plasticity. (Review). Molecular and Cellular Life Science, 57 (11): 1526-1534.

Q Wan, H Y Man, F Liu, J Braunton, H B Niznik, S F Pang, G M Brown and Y T Wang.   1999.   Differential modulation of GABA A receptor function by Mel 1a and Mel 1b receptors. Nature Neuroscience, 2 (5): 401-403

H Y Man, E Ted, L E Becker and Y T Wang.   1998.   Modulation of baroreflex sensitivity by the state of tyrosine phosphorylation in the brainstem of rat.   Brain Research, 792:141-148

Z B Pristupa, F McConkey, F Liu, H Y Man, F J S Lee, Y T Wang and H B Niznik.   1998.   Protein kinase-mediated bidirectional trafficking and functional regulation of the human dopamine transporter.   Synapse, 30:79-87

Q Wan, H Y Man, J Braunton, W Wang, M W Salter, L Becker and Y T Wang.   1997.   Modulation of GABAA receptor function by tyrosine phosphorylation of b subunits.   J Neurosci, 17(13): 5062-5069

Q Wan, Z G Xiong, H Y Man, C A Ackerley, J Brauton, L E Becker, J F MacDonald and Y T Wang.   1997. Recruitment of functional GABAA receptors to postsynaptic domains by insulin.   Nature, 388:686-690