Robert A. Pearce, M.D., Ph.D.

Associate Professor
Department of Anesthesiology and Anatomy
Department of Physiology
rapearce@wisc.edu

www.anesthesia.wisc.edu/pearcelab/index.html

Trainer in the Following Programs:

  • Molecular and Cellular Pharmacology
  • Neuroscience

Honors and Awards:

  • Betty J. Bamforth Research Professor of Anesthesiology

Research Description:

Research in my laboratory is focused upon synaptic inhibition in the central nervous system, and its modulation by general anesthetic agents. Although the precise mechanism of general anesthetic action remains unknown, much evidence indicates that modulation of ion channels underlying inhibitory synaptic transmission plays a key role. The basic properties of the neurotransmitter receptors involved in GABA-mediated inhibitory synaptic transmission, the molecular and cellular alterations brought about by general anesthetics, and the identities of the cells that make up functionally distinct circuits in the hippocampal cortex are areas of active investigation.

General anesthetics prolong the decay of inhibitory currents, as do other drugs that modulate the GABAA receptor, including anxiolytic, sedative-hypnotic, and anticonvulsant medications. However, the molecular mechanisms underlying this common effect may be different for different classes of agents. A primary goal of the research is to identify the effects of different types of drugs on basic molecular events, such as agonist binding, unbinding, and intramolecular transitions between metastable states including open, closed, and desenstitized states. For these experiments we employ a combination of electrophysiological recording and rapid drug application techniques, applied to both native and expressed receptors, to assess the kinetic characteristics of receptors and their modulation by drugs.

A related question under investigation is the relationship between alterations in receptor properties (prolonged decay of the inhibitory
current) and changes in inhibitory circuit function. The preparation used for these studies is the in vitro rat hippocampal brain slice. The hippocampus is a cortical brain region important in learning and memory. It has been studied intensively, so a large amount of information is available about its anatomy and physiology. We are investigating the properties and functions of different types of inhibitory neurons. We have identified two physiologically distinct and anatomically segregated GABAA-mediated synaptic currents whose properties suggest that they play distinct functional roles. We are now studying these synapses using whole cell patch clamp techniques to learn about how their postsynaptic receptors and other factors contribute to their distinct physiological and pharmacological properties, including their responses to anesthetic agents. Also, we are studying the contributions that these synapses make to integrated circuit properties such as network oscillations, by using a combination of physiological recording, antatomical reconstruction, and computer modeling of the circuits involved in generating coordinated network oscillations. By altering receptor properties, anesthetics and other drugs alter information processing, possibly by modifying circuit oscillations, and thereby bring about the desired effects or side-effects of these clinically important agents.

Selected Publications:

  • Hardie JB, Pearce RA. (2006) Active and passive membrane properties and intrinsic kinetics shape synaptic inhibition in hippocampal CA1 pyramidal neurons. J Neurosci. 26(33):8559-69.

  • Boileau AJ, Pearce RA, Czajkowski C. (2006) Tandem subunits effectively constrain GABAA receptor stoichiometry and recapitulate receptor kinetics but are insensitive to GABAA receptor-associated protein. J Neurosci. 25(49):11219-30.

  • Zarnowska ED, Pearce RA, Saad AA, Perouansky M. (2006) The gamma-subunit governs the susceptibility of recombinant gamma-aminobutyric acid type A receptors to block by the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6, 2N). Anesth Analg. 101(2):401-6,

  • Yan Y, Yang D, Zarnowska ED, Du Z, Werbel B, Valliere C, Pearce RA, Thomson JA, Zhang SC. (2005) Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells. 23(6):781-90.

  • Perouansky M, Banks MI, and Pearce RA. (2005). The differential effects of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (F6, 2N) and isoflurane on extrasynaptic g-aminobutyric acid A receptors. Anesth Analg. 100:1667-1673.

  • Gredell JA, Turnquist PA, MacIver MB, and Pearce RA. (2004). Determination of diffusion and partition coefficients of propofol in rat brain tissue: implications for studies of drug action . British J of Anaesthesia 93:810-817.

  • Gredell, J.A., Turnquist, P.A., MacIver, M.B., Pearce, R.A. Determination of diffusion and partition coefficients of propofol in rat brain tissue: implications for studies of drug action . British Journal of Anaesthesia (in press) (2004).

  • Mody, I., and Pearce, R.A. Interneuron diversity series: Diversity of inhibitory neurotransmission through GABAA receptors. Trends in Neuroscience 27:569-575 (2004).

  • Benkwitz, C., Banks, M.I., and Pearce, R.A. Influence of GABAA receptor "2 splice variants on receptor kinetics and isoflurane modulation. Anesthesiology 101:924-936 (2004).

  • Perouansky, M. and Pearce, R.A. Effects on synaptic inhibition in the hippocampus do not underlie the amnestic and convulsive properties of the non-immobilizer 1,2dichlorohexafluorocyclobutane (F6). Anesthesiology 101:66-74 (2004).

  • Boileau, A.J., Li, T.B., Benkwitz, C., Czajkowski, C., and Pearce, R.A. Effects of g2 subunit incorporation on GABAA receptor macroscopic kinetics. Neuropharmacology 44:1003-1012 (2003).

  • Chesney, M.A., Perouansky, M. and Pearce, R.A. Differential uptake of volatile agents into brain tissue in vitro: measurement and application of a diffusion model to determine concentration profiles in brain slices. Anesthesiology 99:122-130 (2003).

  • Eger, E.I. 2nd, Xing, Y., Pearce, R.A., Shafer, S., Laster, M.J., Zhang, Y., Fanselow, M.S., and Sonner, J.M. Isoflurane antagonizes the capacity of flurothyl or 1,2-dichlorohexafluorocyclobutane to impair fear conditioning to context and tone. Anesthesia and Analgesia, 96:1010-1018 (2003).

  • Banks, M.I., Hardie, J.B., and Pearce, R.A. Development of GABAA receptor-mediated inhibitory postsynaptic currents in hippocampus. J. Neurophysiol. 88;3097-3107 (2002).

  • Banks, M.I, Hardie, J.B., and Pearce, R.A. Development of GABAA receptor mediated inhibitory postsynaptic currents in hippocampus. J. Neurophysiology, in press (2002).

  • White, J.A., Banks, M.I., Pearce, R.A., and Kopell, N. Fast and slow GABAA networks of interneurons provide substrate for mixed gamma-theta rhythm. Proceeding of the National Academy of Science 97:8128-8133 (2000).

  • Li, X., Czajkowski, C., and Pearce, R.A. Rapid and direct modulation of GABA-A receptors by halothane. Anesthesiology 92: 1366-1375 (2000).

  • Banks, M.I., White, J.A., Pearce, R.A. Interactions between distinct GABAA circuits in hippocampus. Neuron 25: 449-457 (2000)

  • Banks, M.I. and Pearce, R.A. Kinetic differences between synaptic and extrasynaptic GABAA receptors in CA1 pyramidal cells. J. Neuroscience 20: 937-948 (2000).

  • Li, X.S. and Pearce, R.A. Effects of halothane on GABAA receptor kinetics: evidence for slowed agonist unbinding. J. Neuroscience 20: 899-907 (2000).

  • Banks, M.I., and Pearce, R.A. Dual actions of volatile anesthetics on GABAA receptors: dissociation of blocking and prolonging effects Anesthesiology 90:120-134 (1999).

  • Banks, M.I., Li, T.B., and Pearce, RA. The synaptic basis of GABAA,slow. J. Neuroscience 18:1305-1317 (1998).

Postdoctoral Positions

Postdoctoral Positions:
Two postdoctoral positions are open to study synaptic transmission and postsynaptic receptor properties.

Specific problems include:
1. Study of molecular transitions of the GABAA receptor that occur with channel gating in response to binding of agonist and modulators.
2. Changes in inhibitory circuit function in response to anesthetic agents, particularly with regard to interactions between distinct inhibitory circuits.

Candidates must have a strong background in cellular or molecular neuroscience, and at least two publications in major basic science journals.

Please send curriculum vitae and names of three references to:
Robert A. Pearce, M.D., Ph.D.
Betty J. Bamforth Research Professor of Anesthesiology
University of Wisconsin
1300 Univ. Ave.
Madison, WI 53706
tel. 608-263-4429
fax. 608-262-5558
rapearce@facstaff.wisc.edu