Our long-term objective is to understand how respiratory-related neurons synaptically interact. This application focuses on glycine and gamma-aminobutyric acid (GABA) ligand-gated receptors (glycine-Rs and GABAA-Rs, respectively). We hypothesize that they are important in brainstem and spinal cord physiology related to the neurobiology of breathing. The upper airway is a site of airway obstruction: thus understanding of synaptic transmission to hypoglossal motoneurons (HMs) may provide new insights into airway pathologies such as obstructive sleep apnea. We continue to focus our research on HMs because the tongue has a critical position in the upper airway, thereby affecting upper airway resistance and patency. Also, HMs are important in other behaviors including mastication, swallowing (deglutition), sucking, licking, and vocalization. The experiments proposed employ two different in vitro brainstem slice preparations to study glycinergic and GABAergic synaptic transmission to HMs. In both, rat HMs will be visualized using infra-red differential interference optics and we will use whole-cell and outside-out patch recordings from these neurons. HMs will be studied in the absence (standard slice preparation) and in the presence (rhythmic slice preparation) of ongoing rhythmic respiratory activity.
Specific aim 1 proposes to characterize GABAA -R-mediated synaptic transmission to HMs. We hypothesize that GABAA-Rs have differential pharmacological and kinetic properties as compared to glycine-Rs.
Specific Aim 2 proposes to investigate glycine and GABA cotransmission at individual synaptic terminals apposed to HMs. We hypothesize that glycine and GABA are co-released and that following co-release they activate co-localized glycine and GABAA receptors at individual synaptic terminals.
Specific Aim 3 proposes to investigate whether glycine and/or GABAA receptor mediated synaptic events are important for the respiratory-related behavior of HMs recorded in the rhythmic medullary slice preparation. We hypothesize that glycine and/or GABA mediated synaptic events shape the inspiratory phase behavior of HMs, mostly via shunting inhibition of excitatory respiratory drive. The fourth Specific Aim proposes to investigate in HMs postsynaptic mechanisms whereby ethanol modulates glycine-Rs. We hypothesize that ethanol increases the affinity of glycine-Rs for glycine and thereby potentiates inhibitory synaptic events. This may be an important mechanism whereby alcohol consumption exacerbates obstructive sleep apnea.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS014857-22
Application #
6187049
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Edwards, Emmeline
Project Start
1979-01-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
22
Fiscal Year
2000
Total Cost
$228,973
Indirect Cost
Name
University of Washington
Department
Physiology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Lim, Rebecca; Hoang, Priscilla; Berger, Albert J (2004) Blockade of glycine transporter-1 (GLYT-1) potentiates NMDA receptor-mediated synaptic transmission in hypoglossal motorneurons. J Neurophysiol 92:2530-7
Eggers, Erika D; Berger, Albert J (2004) Mechanisms for the modulation of native glycine receptor channels by ethanol. J Neurophysiol 91:2685-95
Sebe, Joy Y; Eggers, Erika D; Berger, Albert J (2003) Differential effects of ethanol on GABA(A) and glycine receptor-mediated synaptic currents in brain stem motoneurons. J Neurophysiol 90:870-5
O'Brien, J A; Berger, A J (2001) The nonuniform distribution of the GABA(A) receptor alpha 1 subunit influences inhibitory synaptic transmission to motoneurons within a motor nucleus. J Neurosci 21:8482-94
Bou-Flores, C; Berger, A J (2001) Gap junctions and inhibitory synapses modulate inspiratory motoneuron synchronization. J Neurophysiol 85:1543-51
Gibson, I C; Berger, A J (2000) Effect of ethanol upon respiratory-related hypoglossal nerve output of neonatal rat brain stem slices. J Neurophysiol 83:333-42
Berger, A J (2000) Determinants of respiratory motoneuron output. Respir Physiol 122:259-69
Berger, A J; Isaacson, J S (1999) Modulation of motoneuron N-methyl-D-aspartate receptors by the inhibitory neurotransmitter glycine. J Physiol Paris 93:23-7
Singer, J H; Berger, A J (1999) Contribution of single-channel properties to the time course and amplitude variance of quantal glycine currents recorded in rat motoneurons. J Neurophysiol 81:1608-16
O'Brien, J A; Berger, A J (1999) Cotransmission of GABA and glycine to brain stem motoneurons. J Neurophysiol 82:1638-41

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