The proposed studies will answer key questions about molecular and cellular mechanisms that regulate synaptic transmission in brain. The applicant will study the role of postsynaptic Ca2+, protein kinases and protein phosphatases in controlling synaptic transmission. To elucidate postsynaptic mechanisms that regulate synaptic transmission, the applicant will examine intracellular signaling mechanisms downstream of presynaptic transmitter release and postsynaptic receptor activation. He will use specific manipulations of postsynaptic signaling pathways to test the hypothesis that synaptic potentiation requires intracellular Ca2+ release, functional cross-talk among protein kinase and phosphatase pathways and the dynamic balance of spatial and temporal properties of postsynaptic mechanisms controlling synaptic strength by combining (a) visually guided patch-pipette recordings from neuronal cell bodies vs. Dendrites using infrared differential interference contrast microscopy (IR-DIC), and (b) whole-cell pipette-perfusion to control the temporal delivery of modulators of postsynaptic protein kinases and phosphatases and intracellular Ca2+ release. Using whole-cell recordings from dendrites, the applicant will determine if synaptic potentiation can be induced by perfusion of Ca2+/CaM, phosphatase inhibitors, or activators of intracellular Ca2+ release. The experiments will test the hypothesis that dendritic Ca2+ and Ca2+/CaM pathways are responsible for potentiation at central synapses. The applicant will continue examining postsynaptic mechanisms that modulate PPF, and will study mechanisms that modulate PPF at single synapses. Finally, he will analyze developmental changes in the biochemistry of postsynaptic signaling pathways that regulate synaptic potentiation. Experiments will focus on developmental changes in calcineurin properties and its role in postsynaptic mechanisms controlling synaptic plasticity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS032470-05
Application #
2486647
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Broman, Sarah H
Project Start
1994-01-01
Project End
2001-02-28
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Kelly, Paul T; Mackinnon 2nd, Roger L; Dietz, Roger V et al. (2005) Postsynaptic IP3 receptor-mediated Ca2+ release modulates synaptic transmission in hippocampal neurons. Brain Res Mol Brain Res 135:232-48
Maher, Brady J; Mackinnon 2nd, Roger L; Bai, Jihong et al. (2005) Activation of postsynaptic Ca(2+) stores modulates glutamate receptor cycling in hippocampal neurons. J Neurophysiol 93:178-88
Wang, J H; Kelly, P (2001) Calcium-calmodulin signalling pathway up-regulates glutamatergic synaptic function in non-pyramidal, fast spiking rat hippocampal CA1 neurons. J Physiol 533:407-22
Ko, G Y; Kelly, P T (1999) Nitric oxide acts as a postsynaptic signaling molecule in calcium/calmodulin-induced synaptic potentiation in hippocampal CA1 pyramidal neurons. J Neurosci 19:6784-94
Wang, J H; Kelly, P T (1997) Postsynaptic calcineurin activity downregulates synaptic transmission by weakening intracellular Ca2+ signaling mechanisms in hippocampal CA1 neurons. J Neurosci 17:4600-11
Wang, J H; Kelly, P T (1997) Attenuation of paired-pulse facilitation associated with synaptic potentiation mediated by postsynaptic mechanisms. J Neurophysiol 78:2707-16
Wang, J H; Kelly, P T (1996) The balance between postsynaptic Ca(2+)-dependent protein kinase and phosphatase activities controlling synaptic strength. Learn Mem 3:170-81
Wang, J H; Kelly, P T (1996) Regulation of synaptic facilitation by postsynaptic Ca2+/CaM pathways in hippocampal CA1 neurons. J Neurophysiol 76:276-86
Huber, K M; Mauk, M D; Kelly, P T (1995) LTP induced by activation of voltage-dependent Ca2+ channels requires protein kinase activity. Neuroreport 6:1281-4
Huber, K M; Mauk, M D; Thompson, C et al. (1995) A critical period of protein kinase activity after tetanic stimulation is required for the induction of long-term potentiation. Learn Mem 2:81-100

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