To understand learning and memory, we must first elucidate the molecular machinery that regulates synaptic plasticity in the CNS. Recent results indicate that long-term potentiation (LTP), a major form of synaptic plasticity, is not a unitary process, even at a single synapse. LTP is expressed by independent presynaptic and postsynaptic mechanisms at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. Given that the induction of plasticity at these synapses involves the influx of calcium ions into postsynaptic CA1 neurons, the expression of the presynaptic component of LTP suggests the existence of a retrograde signal that transfers a signal from the postsynaptic CA1 neuron to the presynaptic CA3 cell. Various molecular mechanisms have been implicated in retrograde signaling during LTP;however, none alone satisfies all of the requirements. In this proposal, we will examine the roles of nitric oxide, integrins, and neuronal adhesion molecule L1 in mechanisms of retrograde signaling during LTP. To accomplish these goals, we will directly visualize functional changes using fluorescent indicators of presynaptic function at the level of a single synapse. Two-photon laser scanning microscopy and 2-photon laser scanning uncaging techniques will be used in combination with electrophysiological tools in acute hippocampal slices from transgenic mice expressing various fluorescent markers in pyramidal neurons. Relevance: Long-term potentiation (LTP) is the use-dependent enhancement of the signal between neurons in the brain. LTP is thought to be a key process that regulates learning and memory. To better understand learning and memory and further the discovery of ways to prevent disease from disrupting these essential abilities in humans, we will investigate the molecular bases of LTP in mice with appropriate genetic mutations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH079079-05
Application #
8288193
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Asanuma, Chiiko
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$374,220
Indirect Cost
$151,470
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Blundon, Jay A; Zakharenko, Stanislav S (2013) Presynaptic gating of postsynaptic synaptic plasticity: a plasticity filter in the adult auditory cortex. Neuroscientist 19:465-78
Chun, Sungkun; Bayazitov, Ildar T; Blundon, Jay A et al. (2013) Thalamocortical long-term potentiation becomes gated after the early critical period in the auditory cortex. J Neurosci 33:7345-57
Deng, Pan-Yue; Rotman, Ziv; Blundon, Jay A et al. (2013) FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels. Neuron 77:696-711
Lebensburger, Jeffrey D; Howard, Thad; Hu, Yunming et al. (2012) Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin. Blood 119:1915-21
Sperow, Margaret; Berry, Raymond B; Bayazitov, Ildar T et al. (2012) Phosphatase and tensin homologue (PTEN) regulates synaptic plasticity independently of its effect on neuronal morphology and migration. J Physiol 590:777-92
Cho, Jun-Hyeong; Bayazitov, Ildar T; Meloni, Edward G et al. (2012) Coactivation of thalamic and cortical pathways induces input timing-dependent plasticity in amygdala. Nat Neurosci 15:113-22
Blundon, Jay A; Bayazitov, Ildar T; Zakharenko, Stanislav S (2011) Presynaptic gating of postsynaptically expressed plasticity at mature thalamocortical synapses. J Neurosci 31:16012-25
Wei, Peng; Blundon, Jay A; Rong, Yongqi et al. (2011) Impaired locomotor learning and altered cerebellar synaptic plasticity in pep-19/PCP4-null mice. Mol Cell Biol 31:2838-44
Earls, Laurie R; Bayazitov, Ildar T; Fricke, Robert G et al. (2010) Dysregulation of presynaptic calcium and synaptic plasticity in a mouse model of 22q11 deletion syndrome. J Neurosci 30:15843-55
Richardson, Robert J; Blundon, Jay A; Bayazitov, Ildar T et al. (2009) Connectivity patterns revealed by mapping of active inputs on dendrites of thalamorecipient neurons in the auditory cortex. J Neurosci 29:6406-17

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