Unlike many intravenous agents, inhaled anesthetics modulate multiple targets to achieve their effects. Our previous studies showed that amnestic concentrations of isoflurane substantially alter synaptic function mediated by both excitatory A/-methyl-D-aspartate receptors (NMDA-Rs) and inhil)itory v-aminobutyrlc acid type A receptors (GABAA-RS), but that neither action alone is sufficient lo account for the amnestic effect of isoflurane. We propose to study the corribined actions on these two systems, examining several integrative cellular and network processes that support synaptic plasticity and memory encoding by the hippocampus. These studies address the central hypothesis that the combinod action of inhaled anesthetics on excUatop/ and inhibitory siqnslina suppresses learning and ivdmoiv hv inloifeiiiia with dendritic integration dating the initial encoding process leading to synaptic olaslicitv. Thus, Wewill test {1) whether anesthetic tnodulation of inhibition and excitation with selective drugs (alone or in cprnbination) is antagonistic, additive, or synergistic on circuit, network, and behavioral! responses, and whether these actions in combination can account for the amnestic effect of isoflurane;(2) whether circuil-and network-level effects of isoflurane are attenuated in mice carrying genelicalterations that render specific receptors insensitive to inhaled anesthetics;and (3) whether rhythmic fluctuations in excitability dunng oscillatory network states affect the capacity of anesthetics to suppress dendritic integration arid hippocampal plasticity.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM101497-03
Application #
8473886
Study Section
Special Emphasis Panel (ZGM1-PPBC-6 (AN))
Program Officer
Cole, Alison E
Project Start
2011-09-15
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$275,459
Indirect Cost
$67,274
Name
University of Wisconsin Madison
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Zarnowska, E D; Rodgers, F C; Oh, I et al. (2015) Etomidate blocks LTP and impairs learning but does not enhance tonic inhibition in mice carrying the N265M point mutation in the beta3 subunit of the GABA(A) receptor. Neuropharmacology 93:171-8
Rodgers, F Clifford; Zarnowska, Ewa D; Laha, Kurt T et al. (2015) Etomidate Impairs Long-Term Potentiation In Vitro by Targeting α5-Subunit Containing GABAA Receptors on Nonpyramidal Cells. J Neurosci 35:9707-16
Balakrishnan, Shilpashree; Pearce, Robert A (2014) Midazolam and atropine alter theta oscillations in the hippocampal CA1 region by modulating both the somatic and distal dendritic dipoles. Hippocampus 24:1212-31
Balakrishnan, Shilpashree; Pearce, Robert A (2014) Spatiotemporal characteristics and pharmacological modulation of multiple gamma oscillations in the CA1 region of the hippocampus. Front Neural Circuits 8:150
Gemperline, Erin; Laha, Kurt; Scarlett, Cameron O et al. (2014) Measurement of NMDA Receptor Antagonist, CPP, in Mouse Plasma and Brain Tissue Following Systematic Administration Using Ion-Pair LCMS/MS. Anal Methods 6:6389-6396
Dai, Shuiping; Perouansky, Misha; Pearce, Robert A (2012) Isoflurane enhances both fast and slow synaptic inhibition in the hippocampus at amnestic concentrations. Anesthesiology 116:816-23