LTP involves the reorganization of AMPA receptors (AMPARs) in the postsynaptic membrane. Most current work on neural plasticity in mammals involves systems more tractable than intact brain, but it remains unclear how suitable these are as models for brain synapses. Therefore, Specific Aim 1 asks whether synapses in brain resemble synapses in slice-culture or cultured neurons. Excitatory synapses in hippocampus express AMPARs comprising GluR1, GluR2, and GluR3 subunits;GluR2 and GluR3 are trafficked and anchored at the synapse by the same mechanisms, distinct from the mechanisms that handle GluR1.
Specific Aim 2 uses immunogold electron microscopy to gain new insight into the organization of AMPA receptors at the synapse, to determine the organization of AMPAR subunits in a synapse, how their organization changes after LTP and LTD, and where new AMPARs are inserted in the synapse. Spine volume is correlated with the number of AMPA receptors in the synaptic membrane, implying that AMPAR expression must be coupled to spine size. While the causal relationship is not clear, this implies a linkage between the signaling pathways that mediate synaptic plasticity, and those that mediate changes in the actin cytoskeleton.
Specific Aim 3 examines how LIM kinase and Slingshot, two major proteins involved in the control of actin remodeling, are organized in a spine, whether their organization differs between large spines and small spines, and how their organization and level of activation may change after LTP/LTD. These studies will help to elucidate basic mechanisms underlying learning and memory. Their successful completion may help to gain new insight into the biological basis for memory disorders and mental retardation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035527-12
Application #
8204504
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
1998-02-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
12
Fiscal Year
2012
Total Cost
$315,736
Indirect Cost
$85,970
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Ding, Jin-Dong; Kennedy, Mary B; Weinberg, Richard J (2013) Subcellular organization of camkii in rat hippocampal pyramidal neurons. J Comp Neurol 521:3570-83
Hall, Duane D; Dai, Shuiping; Tseng, Pang-Yen et al. (2013) Competition between ?-actinin and Ca²?-calmodulin controls surface retention of the L-type Ca²? channel Ca(V)1.2. Neuron 78:483-97
Kim, Il Hwan; Racz, Bence; Wang, Hong et al. (2013) Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities. J Neurosci 33:6081-92
Racz, Bence; Weinberg, Richard J (2013) Microdomains in forebrain spines: an ultrastructural perspective. Mol Neurobiol 47:77-89
Burette, Alain C; Weinberg, Richard J; Sassani, Patrick et al. (2012) The sodium-driven chloride/bicarbonate exchanger in presynaptic terminals. J Comp Neurol 520:1481-92
Wang, Q; Charych, E I; Pulito, V L et al. (2011) The psychiatric disease risk factors DISC1 and TNIK interact to regulate synapse composition and function. Mol Psychiatry 16:1006-23
Restituito, Sophie; Khatri, Latika; Ninan, Ipe et al. (2011) Synaptic autoregulation by metalloproteases and ýý-secretase. J Neurosci 31:12083-93
Kelm, M Katherine; Weinberg, Richard J; Criswell, Hugh E et al. (2010) The PLC/IP 3 R/PKC pathway is required for ethanol-enhanced GABA release. Neuropharmacology 58:1179-86
Joiner, Mei-ling A; Lise, Marie-France; Yuen, Eunice Y et al. (2010) Assembly of a beta2-adrenergic receptor--GluR1 signalling complex for localized cAMP signalling. EMBO J 29:482-95
Burette, Alain C; Strehler, Emanuel E; Weinberg, Richard J (2009) "Fast" plasma membrane calcium pump PMCA2a concentrates in GABAergic terminals in the adult rat brain. J Comp Neurol 512:500-13

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