Abstract

The proposed research examines the intracellular signaling pathways in cerebellum Purkinje cells implicated in the initiation of long-term depression (LTD)by the conjunctive activation of the climbing fibers (CFs) and the parallel fibers (PFs)excitatory inputs. The specific hypothesis that will be tested is that the associative induction of LTD arises from a convergence between two intracellular signaling pathways, IP3 and calcium ions. More specifically, LTD is induced after CFs raise intracellular calcium sufficiently to permit PF- generated IP3 to release additional calcium from the intracellular stores within the postsynaptic spines of the Purkinje cells. The proposal has four specific aims to investigate: 1)the role of metabotropic glutamate receptors (mGluR)in PF signaling; 2)the role of calcium from IP3- sensitive internal stores in the induction of LTD; 3)the regulation of calcium release from IP3 sensitive stores by calcium levels; and 4)if LTD occurs after CFs raise intracellular calcium levels sufficiently to permit PF-generated IP3 to release more calcium from intracellular stores. The investigators seek to achieve these objectives through a series of experiment using rat cerebellar slices. The applicant's expertise with whole-cell recordings, ion imaging, confocal microscopy, and localized flash photolysis will be applied in these experiments.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034045-04
Application #
2669056
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Baughman, Robert W
Project Start
1995-04-01
Project End
1999-02-28
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Duke University
Department
Biology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Santamaria, Fidel; Wils, Stefan; De Schutter, Erik et al. (2011) The diffusional properties of dendrites depend on the density of dendritic spines. Eur J Neurosci 34:561-8
Tanaka, Keiko; Augustine, George J (2008) A positive feedback signal transduction loop determines timing of cerebellar long-term depression. Neuron 59:608-20
Tanaka, Keiko; Khiroug, Leonard; Santamaria, Fidel et al. (2007) Ca2+ requirements for cerebellar long-term synaptic depression: role for a postsynaptic leaky integrator. Neuron 54:787-800
Santamaria, Fidel; Wils, Stefan; De Schutter, Erik et al. (2006) Anomalous diffusion in Purkinje cell dendrites caused by spines. Neuron 52:635-48
Augustine, George J; Santamaria, Fidel; Tanaka, Keiko (2003) Local calcium signaling in neurons. Neuron 40:331-46
Ozen, G; Augustine, G J; Hall, W C (2000) Contribution of superficial layer neurons to premotor bursts in the superior colliculus. J Neurophysiol 84:460-71
Kuner, T; Augustine, G J (2000) A genetically encoded ratiometric indicator for chloride: capturing chloride transients in cultured hippocampal neurons. Neuron 27:447-59
Wang, S S; Khiroug, L; Augustine, G J (2000) Quantification of spread of cerebellar long-term depression with chemical two-photon uncaging of glutamate. Proc Natl Acad Sci U S A 97:8635-40
Pettit, D L; Helms, M C; Lee, P et al. (1999) Local excitatory circuits in the intermediate gray layer of the superior colliculus. J Neurophysiol 81:1424-7
Womack, M; Thompson, K; Fanselow, E et al. (1998) Elevated intracellular calcium levels in cerebellar granule neurons of weaver mice. Neuroreport 9:3391-5

Showing the most recent 10 out of 16 publications