The goals of the proposed experiments are to obtain information about the basic mechanisms underlying long-term changes in the synaptic properties of mammalian CNS neurons. Such long-term alterations are thought to be responsible for the enduring enhancement in the efficacy of synaptic transmission underlying learning and memory formation. The present study will examine the role of intraneuronal Ca2+ homeostasis, in particular the contribution of Ca2+ sequestering organelles, to the control of synaptic excitability. Long-term potentiation (LTP), a use-dependent increase in synaptic efficacy critically linked to Ca2+, will serve as the model for plastic cellular alterations. The study will take advantage of the newly developed whole-cell patch clamp recording technique in conventional brain slice preparations. In addition to improving the quality and resolution of electrophysiological recordings, this technique is best suited for introducing chemicals and drugs into the neurons' internal environment. Whole-cell patch (current- and voltage-clamp) and extracellular recordings will be obtained in neurons of the rat hippocampal formation. Spontaneous or evoked excitatory or inhibitory postsynaptic currents will be recorded under various conditions of intraneuronal Ca2+ homeostasis. LTP will be induced by tetanic stimulation of afferent pathways. Considering the ubiquitous role of Ca2+ in regulating cellular function, the modulation of synaptic events by Ca2+ originating from Ca2+-sequencing organelles will be especially emphasised. This can be accomplished by studying how intraneuronally applied chemicals, which alter the release of Ca2+ from intracellular sequestering organelles, modify basal or long-term potentiated synaptic responses. Furthermore, the induction and maintenance phases of currents and fluctuations in steady excitatory current noise in potentiated neurons will permit the examination of long-term synaptic alterations at the single receptor/channel level. The study proposes to establish the nature of the relationship between intraneuronal Ca2+ homeostasis and the control of synaptic excitability intrinsic to the nervous system. The regulation of neuronal excitability by Ca2+ released from the neuronal endoplasmic reticulum or other Ca2+ sequestering organelles has not yet been investigated in detail. Only recently, by analogy to the function of the sarcoplasmic reticulum in muscle, studies have begun to stress the importance of Ca2+ buffering and release mechanisms in neurons. By extending these novel findings and examining previously unexplored aspects of intraneuronal Ca2+ homeostasis, the present experiments will provide a better understanding of the long-term regulation of neuronal function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027528-03
Application #
3413826
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1990-08-01
Project End
1993-01-31
Budget Start
1992-08-01
Budget End
1993-01-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Faas, Guido C; Mody, Istvan (2012) Measuring the kinetics of calcium binding proteins with flash photolysis. Biochim Biophys Acta 1820:1195-204
Faas, Guido C; Raghavachari, Sridhar; Lisman, John E et al. (2011) Calmodulin as a direct detector of Ca2+ signals. Nat Neurosci 14:301-4
Gordey, M; Mekmanee, L; Mody, I (2001) Altered effects of ethanol in NR2A(DeltaC/DeltaC) mice expressing C-terminally truncated NR2A subunit of NMDA receptor. Neuroscience 105:987-97
Otis, T S; De Koninck, Y; Mody, I (1994) Lasting potentiation of inhibition is associated with an increased number of gamma-aminobutyric acid type A receptors activated during miniature inhibitory postsynaptic currents. Proc Natl Acad Sci U S A 91:7698-702
Mody, I; De Koninck, Y; Otis, T S et al. (1994) Bridging the cleft at GABA synapses in the brain. Trends Neurosci 17:517-25
Mody, I; Staley, K J (1994) Cell properties in the epileptic hippocampus. Hippocampus 4:275-80
De Koninck, Y; Mody, I (1994) Noise analysis of miniature IPSCs in adult rat brain slices: properties and modulation of synaptic GABAA receptor channels. J Neurophysiol 71:1318-35
Soltesz, I; Zhou, Z; Smith, G M et al. (1994) Rapid turnover rate of the hippocampal synaptic NMDA-R1 receptor subunits. Neurosci Lett 181:5-8
Kohr, G; Mody, I (1994) Kindling increases N-methyl-D-aspartate potency at single N-methyl-D-aspartate channels in dentate gyrus granule cells. Neuroscience 62:975-81
Mody, I; Soltesz, I (1993) Activity-dependent changes in structure and function of hippocampal neurons. Hippocampus 3 Spec No:99-111

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