Glutamate mediates rapid synaptic responses in many parts of the vertebrate nervous system. While activation of the AMPA subtype of glutamate receptor requires a high concentration of transmitter, these receptors desensitize to low concentrations, a process which contributes significantly to determining the amplitude and decay time of synaptic responses. Additionally, the NMDA and metabotropic glutamate receptors are activated by low concentrations of transmitter. As the only known mechanism for removing glutamate from the extracellular space is uptake by pumps, glutamate could diffuse from the synaptic cleft, influencing the activity of surrounding synapses by binding to such high affinity sites. In order to understand how the transmitter could have such widespread effects, we must answer several questions. How much glutamate is released? How far can it diffuse from the synapse? What are its actions outside the cleft"""""""" Do glutamate pumps limits its sphere of influence and its lifetime? The neurons in the chick nucleus magnocellularis are well suited to studying these issues. The neurons are adendritic and receive several large excitatory axon terminals, as well as inhibitory boutons, on the cell body. These inputs can be stimulated separately. Glutamate released by the excitatory synapse may require tens of milliseconds to be removed. We will use the these cells in slices and as dissociated cells in the proposed experiments. Glutamate concentration in the synaptic cleft will be assayed by a novel, empirical method which takes advantage of voltage-sensitive channel kinetics of the AMPA receptor and the dependence of those kinetics on concentration. Glutamate outside the synaptic cleft will be detected cy the calibrated response of receptor-rich membrane patches positioned near the synapse. Additionally, we will determine the biological actions of diffusing transmitter on adjacent excitatory and inhibitory synapses. The role of glutamate uptake in regulating the lifetime of glutamate in the cleft and outside the cleft will be assayed. The site of uptake in this system, whether pre- or postsynaptic or glial, will be determined. Finally, the buffering of the transmitter by binding to receptors will be explored as it relates to controlling the lifetime of the transmitter in the cleft.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS028901-05
Application #
2267280
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1991-05-01
Project End
1999-04-30
Budget Start
1995-05-01
Budget End
1996-04-30
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Physiology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Lu, Hsin-Wei; Balmer, Timothy S; Romero, Gabriel E et al. (2017) Slow AMPAR Synaptic Transmission Is Determined by Stargazin and Glutamate Transporters. Neuron 96:73-80.e4
Irie, Tomohiko; Trussell, Laurence O (2017) Double-Nanodomain Coupling of Calcium Channels, Ryanodine Receptors, and BK Channels Controls the Generation of Burst Firing. Neuron 96:856-870.e4
Tang, Zheng-Quan; Trussell, Laurence O (2017) Serotonergic Modulation of Sensory Representation in a Central Multisensory Circuit Is Pathway Specific. Cell Rep 20:1844-1854
Lu, Hsin-Wei; Trussell, Laurence O (2016) Spontaneous Activity Defines Effective Convergence Ratios in an Inhibitory Circuit. J Neurosci 36:3268-80
Balmer, Timothy S; Trussell, Laurence O (2016) Quantum Disentanglement: Electrical Analysis of the Complex Roles of Ions in Filling Vesicles with Glutamate. Neuron 90:667-9
Borges-Merjane, Carolina; Trussell, Laurence O (2015) ON and OFF unipolar brush cells transform multisensory inputs to the auditory system. Neuron 85:1029-42
Tang, Zheng-Quan; Trussell, Laurence O (2015) Serotonergic regulation of excitability of principal cells of the dorsal cochlear nucleus. J Neurosci 35:4540-51
Apostolides, Pierre F; Trussell, Laurence O (2014) Chemical synaptic transmission onto superficial stellate cells of the mouse dorsal cochlear nucleus. J Neurophysiol 111:1812-22
Huang, Hai; Trussell, Laurence O (2014) Presynaptic HCN channels regulate vesicular glutamate transport. Neuron 84:340-6
Apostolides, Pierre F; Trussell, Laurence O (2014) Superficial stellate cells of the dorsal cochlear nucleus. Front Neural Circuits 8:63

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