There is compelling evidence for the involvement of presynaptic inhibition in controlling normal synaptic transmission and preventing excessive neurotransmitter release at mammalian central synapses. The presynaptic site is an effective target for modulation of synaptic transmission and presynaptic voltage-dependent calcium channels play a significant role in controlling transmitter release. To address our long-term objective of understanding the basic presynaptic mechanisms underlying modulation of synaptic transmission in mammalian central synapses, we propose to investigate the direct and indirect role of presynaptic calcium during inhibition of synaptic transmission at hippocampal CA3/CA1, MF/CA3 and PP/GC excitatory synapses. This in vitro study will employ hippocampal brain slices and optical imaging techniques. We will selectively load presynaptic terminals with ion-sensitive indicators to investigate resting levels and transients of presynaptic calcium and presynaptic potassium. In addition, we will use voltage- sensitive dyes to measure presynaptic action potentials. Specific blockers will be utilized to identify and quantify the types of presynaptic voltage-dependent calcium channels involved in synaptic transmission. We will study presynaptic calcium during the application of neuromodulators with presumed inhibitory presynaptic action and identify the types of calcium channels involved and their quantitative inhibition. Through the use of advanced optical techniques, the proposed studies will provide new and important insight into the presynaptic modulation of mammalian synaptic transmission. This insight will contribute to the understanding of normal and pathological synaptic transmission. Excessive release of excitatory neurotransmitter has been observed during episodes of epilepsy and after brain damage. Control of this release by presynaptically acting endogenous neuromodulators could be the basis of future therapeutic interventions. We will address the following specific aims: 1) To discriminate the types of presynaptic VDCCs at principal hippocampal excitatory synapses. 2) To investigate resting levels and influx of presynaptic Ca2+ during presynaptic inhibition of evoked synaptic transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033147-06
Application #
6393671
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Talley, Edmund M
Project Start
1995-08-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
6
Fiscal Year
2001
Total Cost
$225,604
Indirect Cost
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Hoogland, Tycho M; Saggau, Peter (2004) Facilitation of L-type Ca2+ channels in dendritic spines by activation of beta2 adrenergic receptors. J Neurosci 24:8416-27
McQuiston, A Rory; Saggau, Peter (2003) Mu-opioid receptors facilitate the propagation of excitatory activity in rat hippocampal area CA1 by disinhibition of all anatomical layers. J Neurophysiol 90:1936-48
Faas, Guido C; Adwanikar, Hita; Gereau 4th, Robert W et al. (2002) Modulation of presynaptic calcium transients by metabotropic glutamate receptor activation: a differential role in acute depression of synaptic transmission and long-term depression. J Neurosci 22:6885-90
Xiong, Z Q; Saggau, P; Stringer, J L (2000) Activity-dependent intracellular acidification correlates with the duration of seizure activity. J Neurosci 20:1290-6
Qian, J; Saggau, P (1999) Modulation of transmitter release by action potential duration at the hippocampal CA3-CA1 synapse. J Neurophysiol 81:288-98
Saggau, P; Gray, R; Dani, J A (1999) Optical measurements of calcium signals in mammalian presynaptic terminals. Methods Enzymol 294:3-19
Bullen, A; Saggau, P (1999) High-speed, random-access fluorescence microscopy: II. Fast quantitative measurements with voltage-sensitive dyes. Biophys J 76:2272-87
Qian, J; Saggau, P (1999) Activity-dependent modulation of K+ currents at presynaptic terminals of mammalian central synapses. J Physiol 519 Pt 2:427-37
Sinha, S R; Saggau, P (1999) Simultaneous optical recording of membrane potential and intracellular calcium from brain slices. Methods 18:204-14, 175
Bullen, A; Saggau, P (1998) Indicators and optical configuration for simultaneous high-resolution recording of membrane potential and intracellular calcium using laser scanning microscopy. Pflugers Arch 436:788-96

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