Throughout the nervous system, GABAA receptor-mediated inhibition controls neuronal network activity. Within the hippocampus, diverse interneurons that utilize a variety of GABAA receptor subtypes control and coordinate activity in circuits that play crucial roles in learning and memory. These circuits are also susceptible to pathological changes in conditions such as Alzheimer's disease and epilepsy, and the receptors that they utilize are the targets of many clinically used drugs;understanding their organization and function are directly relevant to human health. We propose to test the hypothesis that receptors containing the GABAA receptor a5 and 03 subunits, which are heavily expressed in the dendritic layers of the hippocampal CA1 region, contribute to slow synaptic inhibition, that they are instrumental in controlling responses to repetitive stimulation, and that they participate in the generation or expression of network oscillations. To test these hypotheses we have identified three specific aims: 1) test the contributions of ct5 and (33 subunits to inhibition in hippocampal pyramidal neurons in vitro;2) test the contributions of a5 and (33 subunits to integrative cellular properties and network function in the hippocampus in vitro;and 3) test the contributions of a5 and (33 subunits to hippocampal network oscillations. To accomplish these aims we will follow a combined genetic and pharmacologic approach, using gene-targeted mice and drugs that have intrinsic subunit selectivity or are rendered selective by subunit-specific mutations. The long term-goal of this research is to relate the properties of individual subunits and synapses to activity patterns and network responses that underlie cognitive functions such as learning and memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056411-04
Application #
7770780
Study Section
Special Emphasis Panel (ZRG1-SBIB-E (02))
Program Officer
Stewart, Randall R
Project Start
2007-03-01
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2012-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$318,348
Indirect Cost
Name
University of Wisconsin Madison
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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
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
Pearce, R A; Duscher, P; Van Dyke, K et al. (2012) Isoflurane impairs odour discrimination learning in rats: differential effects on short- and long-term memory. Br J Anaesth 108:630-7
Perouansky, Misha; Pearce, Robert A (2011) How we recall (or don't): the hippocampal memory machine and anesthetic amnesia. Can J Anaesth 58:157-66
Hall, Michael A; Xi, Jin; Lor, Chong et al. (2010) m-Azipropofol (AziPm) a photoactive analogue of the intravenous general anesthetic propofol. J Med Chem 53:5667-75
Perouansky, Misha; Rau, Vinuta; Ford, Tim et al. (2010) Slowing of the hippocampal ? rhythm correlates with anesthetic-induced amnesia. Anesthesiology 113:1299-309
Blake, Alexander J; Rodgers, Frank C; Bassuener, Anna et al. (2010) A microfluidic brain slice perfusion chamber for multisite recording using penetrating electrodes. J Neurosci Methods 189:5-13
Ferrarelli, Fabio; Massimini, Marcello; Sarasso, Simone et al. (2010) Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness. Proc Natl Acad Sci U S A 107:2681-6
Dai, Shuiping; Perouansky, Misha; Pearce, Robert A (2009) Amnestic concentrations of etomidate modulate GABAA,slow synaptic inhibition in hippocampus. Anesthesiology 111:766-73

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