Neurons in the avian nucleus magnocellularis and mammalian ventral cochlear nucleus passage the timing of phase-locked action potentials with great precision. Their ability to preserve timing is made possible by a variety of cellular adaptations at the membrane level, and is essential for the key role of these neurons in the localization of sound. While these neurons have long been known to be contacted by GABAergic axons, the function of such putatively inhibitory inputs is poorly understood. This is important to clarify in part because GABA receptors are a common pharmacological target and are implicated in a variety of neurological disorders. The goal of the proposed research is to determine how synaptically-released GABA can modify signals generated by auditory nerve fibers. This will be accomplished using a brain slice preparation of the chick nucleus magnocellularis in which individual cells will be patch clamped, and single excitatory and inhibitory presynaptic axons separately stimulated. We will determine the mechanisms of GABA release and postsynaptic GABA action by monitoring of postsynaptic GABAA receptor activation while measuring presynaptic calcium accumulation of GABAergic synapses, exploring a newly discovered phenomenon that GABA release from the synapses becomes desynchronized during stimulus trains. We will also use stimulation of excitatory and inhibitory fibers to determine how the synapses interact, either at the postsynaptic, electrical level, or at the presynaptic level through transmitter diffusion to presynaptic modulatory receptors of the GABAB subtype. The kinetics of activation of GABA receptors will be determined using rapid release of chemically-caged neurotransmitter in order to determine the relative time scales of pre- and postsynaptic actions of the GABA. This work will also examine the observation that presynaptic GABA receptors can have a potentiating effect of excitatory transmission in the cochlear nucleus, apparently at odds with the classical inhibitory role ascribed to GABA. The proposed research will clarify how GABA can facilitate the relay functions of these neurons and provide new clues as to how GABAergic drugs might modify sensory processing in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC004450-03
Application #
6379548
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Freeman, Nancy
Project Start
1999-09-01
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
3
Fiscal Year
2001
Total Cost
$176,527
Indirect Cost
Name
Oregon Health and Science University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
Joris, Philip X; Trussell, Laurence O (2018) The Calyx of Held: A Hypothesis on the Need for Reliable Timing in an Intensity-Difference Encoder. Neuron 100:534-549
Moore, Alexandra K; Weible, Aldis P; Balmer, Timothy S et al. (2018) Rapid Rebalancing of Excitation and Inhibition by Cortical Circuitry. Neuron 97:1341-1355.e6
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
Moore, Lucille A; Trussell, Laurence O (2017) Corelease of Inhibitory Neurotransmitters in the Mouse Auditory Midbrain. J Neurosci 37:9453-9464
Yaeger, Daniel B; Trussell, Laurence O (2016) Auditory Golgi cells are interconnected predominantly by electrical synapses. J Neurophysiol 116:540-51
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

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