In the central nervous system, a neuron receives a large number of synaptic inputs from many surrounding cells, with individual synapses acting independently of one another. Synaptic plasticity, which is essential for high brain functions including learning and memory, is a synapse autonomous event under physiological conditions. A large amount of data has shown that both Hebbian-type synaptic plasticity including long-term potentiation (LTP) and long-term depression (LTD), as well as non-Hebbian type homeostatic synaptic plasticity are expressed via regulation of synaptic AMPA receptor (AMPAR) abundance, often by vesicle-mediated receptor trafficking. Given the fact that plasticity is highly synapse specific, investigation of synapse specific, activity-dependent regulation of AMPAR expression will provide crucial insights in our understanding of synapse physiology and brain function. Furthermore, homeostatic plasticity has been studied only at the neuronal population level;if and how it is expressed at single synapses remains elusive. To address these issues, we have set up two experimental paradigms in neuronal culture, in which activity levels of identifiable single synapses are specifically regulated. We will investigate the cellular mechanisms by which AMPAR abundance is specifically regulated in response to activity changes at single synapses. The application aims to understand the mechanisms by which the strength of intercellular communication is regulated in neurons. By investigating synapse specific, activity-dependent regulation of AMPAR expression, this study will provide crucial insights in our understanding of synapse physiology and brain function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH079407-05
Application #
8309377
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Asanuma, Chiiko
Project Start
2008-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$361,969
Indirect Cost
$139,219
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Lin, Amy; Man, Heng-Ye (2014) Endocytic adaptor epidermal growth factor receptor substrate 15 (Eps15) is involved in the trafficking of ubiquitinated ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. J Biol Chem 289:24652-64
Lin, Amy W; Man, Heng-Ye (2013) Ubiquitination of neurotransmitter receptors and postsynaptic scaffolding proteins. Neural Plast 2013:432057
Van Maldergem, Lionel; Hou, Qingming; Kalscheuer, Vera M et al. (2013) Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth. Hum Mol Genet 22:3306-14
Man, Heng-Ye; Ma, Xin-Ming (2012) A role for neuroserpin in neuron morphological development. J Neurochem 121:495-6
Jarzylo, Larissa A; Man, Heng-Ye (2012) Parasynaptic NMDA receptor signaling couples neuronal glutamate transporter function to AMPA receptor synaptic distribution and stability. J Neurosci 32:2552-63
Amato, Stephen; Man, Heng-Ye (2011) Bioenergy sensing in the brain: the role of AMP-activated protein kinase in neuronal metabolism, development and neurological diseases. Cell Cycle 10:3452-60
Man, Heng-Ye (2011) GluA2-lacking, calcium-permeable AMPA receptors--inducers of plasticity? Curr Opin Neurobiol 21:291-8
Hou, Qingming; Gilbert, James; Man, Heng-Ye (2011) Homeostatic regulation of AMPA receptor trafficking and degradation by light-controlled single-synaptic activation. Neuron 72:806-18
Lin, Amy; Hou, Qingming; Jarzylo, Larissa et al. (2011) Nedd4-mediated AMPA receptor ubiquitination regulates receptor turnover and trafficking. J Neurochem 119:27-39
Zhang, Dawei; Hou, Qingming; Wang, Min et al. (2009) Na,K-ATPase activity regulates AMPA receptor turnover through proteasome-mediated proteolysis. J Neurosci 29:4498-511