Research

Research in my laboratory is focused on understanding the mechanisms by which general anesthetics alter central nervous system function. Although the precise mechanisms remain 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.

Many general anesthetics enhance GABA receptor, as do a wide variety of other medications, including anxiolytic, sedative-hypnotic, and anticonvulsant agents. The molecular mechanisms underlying these common effects may differ for different classes of agents. One primary goal is to identify the basic molecular events that occur during receptor activation, such as agonist binding, unbinding, and intra-molecular transitions between metastable states, and how they are affected by different classes of drugs. For these experiments we employ a combination of electrophysiological recording and rapid drug application techniques, applied to both native and expressed receptors.

A related question is the relationship between altered receptor properties, such as prolonged decay of inhibitory currents, and changes in inhibitory circuit function. Using hippocampal brain slice preparations and multichannel in vivo recordings from the hippocampus of genetically altered mice we are trying to understand how different inhibitory circuits found in this part of the brain support and control complex functions such as learning and memory. We are particularly interested in the cellular and molecular components and network functions of different types of synapses that are found on the dendrites versus the somata of pyramidal neurons and interneurons, and their roles in generating or controlling network synchrony that underlies rhythmic activity patterns such as theta and gamma 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.